# Patent

## Title
Substituted phenylacetate and phenylpropane amides and use thereof

## Abstract

The present application relates to novel substituted phenylacetamides and phenylpropanamides, to processes for preparing them, to their use alone or in combinations for the treatment and/or prevention of diseases and also to their use for the production of medicaments for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.

## Background
The present application relates to novel substituted phenylacetamides and phenylpropanamides, to processes for preparing them, to their use alone or in combinations for the treatment and/or prevention of diseases and also to their use for the production of medicaments for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.
The liquid content of the human body is subject to various physiological control mechanisms whose purpose is to keep it constant (volume homeostasis). In the process, both the volume filling of the vascular system and also the osmolarity of the blood plasma are continuously recorded by appropriate sensors (baroreceptors and osmoreceptors). The information which these sensors supply to the relevant centres in the brain regulates drinking behaviour and controls fluid excretion via the kidneys by means of humoral and neural signals. The peptide hormone vasopressin is of central importance in this [Schrier R. W., Abraham, W. T., New Engl. J. Med. 341, 577-585 (1999)].
Vasopressin is produced in specialized endocrine neurons in the nucleus supraopticus and n. para-ventricularis in the wall of the third ventricle (hypothalamus) and transported from there along its neural processes into the posterior lobes of the hypophysis (neurohypophysis). There the hormone is released into the bloodstream according to stimulus. A loss of volume, e.g. as a result of acute bleeding, heavy sweating, prolonged thirst or diarrhoea, is a stimulus for intensified outpouring of the hormone. Conversely, the secretion of vasopressin is inhibited by an increase in the intravascular volume, e.g. as result of increased fluid intake.
Vasopressin exerts its action mainly via binding to three receptors, which are classified as V1a, V1b and V2 receptors and belong to the family of G protein-coupled receptors. V1a receptors are mainly located on the cells of the vascular smooth musculature. Their activation gives rise to vasoconstriction, as a result of which the peripheral resistance and blood pressure rise. Apart from this, V1a receptors are also detectable in the liver. V1b receptors (also named V3 receptors) are detectable in the central nervous system. Together with corticotropin-releasing hormone (CRH), vasopressin regulates the basal and stress-induced secretion of adrenocorticotropic hormone (ACTH) via the V1b receptor. V2 receptors are located in the distal tubular epithelium and the epithelium of the collecting tubules in the kidney. Their activation renders these epithelia permeable to water. This phenomenon is due to the incorporation of aquaporins (special water channels) in the luminal membrane of the epithelial cells.
The importance of vasopressin for the reabsorption of water from the urine in the kidney becomes clear from the clinical picture of diabetes insipidus, which is caused by a deficiency of the hormone, e.g. owing to hypophysis damage. Patients who suffer from this clinical picture excrete up to 20 liters of urine per 24 hours if they are not given replacement hormone. This volume corresponds to about 10% of the primary urine. Because of its great importance for the reabsorption of water from the urine, vasopressin is also synonymously referred to as antidiuretic hormone (ADH). Logically, pharmacological inhibition of the action of vasopressin/ADH on the V2 receptor results in increased urine excretion. In contrast to the action of other diuretics (thiazides and loop diuretics), however, V2 receptor antagonists cause increased water excretion, without substantially increasing the excretion of electrolytes. This means that by means of V2 antagonist drugs, volume homeostasis can be restored, without in the process affecting electrolyte homeostasis. Hence drugs with V2 antagonist activity appear particularly suitable for the treatment of all disease conditions which are associated with an overloading of the body with water, without the electrolytes being effectively increased in parallel. A significant electrolyte abnormality is measurable in clinical chemistry as hyponatraemia (sodium concentration <135 mmol/L); it is the most important electrolyte abnormality in hospital patients, with an incidence of about 5% or 250 000 cases per year in the USA alone. If the plasma sodium concentration falls below 115 mmol/L, comatose states and death are imminent.
Depending on the underlying cause, a distinction is made between hypovolaemic, euvolaemic and hypervolaemic hyponatraemia. The forms of hypervolaemia with oedema formation are clinically significant. Typical examples of this are the syndrome of inadequate ADH/vasopressin secretion (SIAD) (e.g. after craniocerebral trauma or as paraneoplasia in carcinomas) and hypervolaemic hyponatraemia in liver cirrhosis, various renal diseases and heart failure [De Luca L. et al., Am. J. Cardiol. 96 (suppl.), 19L-23L (2005)]. In particular, patients with heart failure, in spite of their relative hyponatraemia and hypervolaemia, often display elevated vasopressin levels, which is seen as the consequence of generally disturbed neurohumoral regulation in heart failure [Francis G. S. et al., Circulation 82, 1724-1729 (1990)].
The disturbed neurohormonal regulation essentially manifests itself in an elevation of the sympathetic tone and inappropriate activation of the renin-angiotensin-aldosterone system. While the inhibition of these components by beta-receptor blockers on the one hand and by ACE inhibitors or angiotensin-receptor blockers on the other is now an inherent part of the pharmacological treatment of heart failure, the inappropriate elevation of vasopressin secretion in advanced heart failure is at present still not adequately treatable. Apart from the retention of water mediated by V2 receptors and the unfavourable haemodynamic consequences associated therewith in terms of increased backload, the emptying of the left ventricle, the pressure in the pulmonary blood vessels and cardiac output are also adversely affected by V1a-mediated vasoconstriction.
Furthermore, on the basis of experimental data in animals, a direct hypertrophy-promoting action on the heart muscle is also attributed to vasopressin. In contrast to the renal effect of volume expansion, which is mediated by activation of V2 receptors, the direct action on the heart muscle is triggered by activation of V1a receptors.
For these reasons, substances which inhibit the action of vasopressin on the V2 and/or on the V1a receptor appear suitable for the treatment of heart failure. In particular, compounds with combined activity on both vasopressin receptors (V1a and V2) should both have desirable renal and also haemodynamic effects and thus offer an especially ideal profile for the treatment of patients with heart failure. The provision of such combined vasopressin antagonists also appears to make sense inasmuch as a volume diminution mediated solely via V2 receptor blockade can entail the stimulation of osmoreceptors and as a result a further compensatory increase in vasopressin release. As a result, in the absence of a component simultaneously blocking the V1a receptor, the harmful effects of the vasopressin, such as for example vasoconstriction and heart muscle hypertrophy, could be further intensified [Saghi P. et al., Europ. Heart J. 26, 538-543 (2005)].
WO 99/54315 discloses substituted triazolones having neuroprotective action, and WO 2006/117657 describes triazolone derivatives as antiinflammatory agents. Furthermore, EP 503 548-A1 and EP 587 134-A2 claim cyclic urea derivatives and their use for the treatment of thromboses. Substituted triazolthiones as ion channel modulators are disclosed in WO 2005/097112. WO 2007/134862 describes substituted imidazol-2-ones and 1,2,4-triazolones as vasopressin receptor antagonists for the treatment of cardiovascular disorders. Variously substituted triazolones as vasopressin receptor antagonists are disclosed in WO 2010/105770, WO 2010/105750, WO 2011/104322 and WO 2011/023703.
It was an object of the present invention to provide novel compounds which act as potent selective, dual V1a/V2 receptor antagonists and have increased solubility in aqueous media, and as such are suitable for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.
The present invention provides compounds of the general formula (I)




in which

    A represents a bond or C(R6AR6B)—,
    
        where
        R6A represents hydrogen, (C1-C4)-alkyl or trifluoromethyl,
        R6B represents hydrogen or (C1-C4)-alkyl,
    
    
    R1 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C3-C7)-cycloalkyl,
    
        where (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of deuterium, halogen, cyano, oxo, hydroxy, trifluoromethyl, (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, trifluoromethoxy and phenyl,
        
            in which (C3-C7)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C1-C4)-alkyl, oxo, hydroxy, (C1-C4)-alkoxy and amino,
            and
            in which (C1-C6)-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of amino, hydroxy, (C1-C4)-alkoxy, hydroxycarbonyl and (C1-C4)-alkoxycarbonyl
            and
            in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C1-C4)-alkyl, trifluoromethyl, hydroxy, hydroxymethyl, (C1-C4)-alkoxy, trifluoromethoxy, (C1-C4)-alkoxymethyl, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl and di-(C1-C4)-alkylaminocarbonyl,
        
        
        and
        where (C3-C7)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxy, amino and oxo,
    
    
    R2 represents benzothienyl, phenyl, thienyl or furyl,
    
        where benzothienyl, phenyl, thienyl and furyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C1-C4)-alkyl, trifluoromethyl, hydroxy, (C1-C4)-alkoxy and trifluoromethoxy,
    
    
    R3 represents a group of the formula






where

    # represents the point of attachment to the nitrogen atom,
    L represents (C1-C4)-alkanediyl,
    
        where (C1-C4)-alkanediyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine and (C1-C4)-alkyl,
    
    
    R7A represents hydrogen or (C1-C4)-alkyl,
    R7B represents hydrogen or (C1-C4)-alkyl,

or

    R7A and R7B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle,
    R8 represents hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl,
    R9 represents hydroxy, trifluoromethoxy, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl,
    R4 represents phenyl, naphthyl or 5- to 10-membered heteroaryl, where phenyl, naphthyl and 5- to 10-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy, (C1-C4)-alkoxy, difluoromethoxy and trifluoromethoxy,
    R5 represents hydrogen, deuterium, trifluoromethyl or (C1-C4)-alkyl,

and their salts, solvates and solvates of the salts.



Compounds according to the invention are the compounds of the formula (I) and their salts, solvates, and solvates of the salts; the compounds of the below-specified formulae embraced by formula (I), and their salts, solvates, and solvates of the salts; and also the compounds specified below as working examples and embraced by formula (I), and their salts, solvates, and solvates of the salts; insofar as the below-specified compounds embraced by formula (I) are not already salts, solvates, and solvates of the salts.
Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the invention are also included.
Physiologically acceptable salts of the compounds according to the invention include acid addition salts of conventional mineral acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid.
Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of example and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanol-amine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
Solvates in the context of the invention are designated as those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.
The compounds according to the invention can exist in different stereoisomeric forms depending on their structure, i.e. in the form of configuration isomers or optionally also as conformation isomers (enantiomers and/or diastereomers, including those in the case of atropisomers). The present invention therefore includes the enantiomers and diastereomers and their particular mixtures. The stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this, in particular HPLC chromatography on an achiral or chiral phase.
Where the compounds according to the invention can occur in tautomeric forms, the present invention includes all the tautomeric forms.
The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 129I and 131I. Particular isotopic variants of a compound according to the invention, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with 3H or 14C isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the compounds according to the invention may therefore in some cases also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by generally used processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
The present invention moreover also includes prodrugs of the compounds according to the invention. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their dwell time in the body.
In the context of the present invention, the substituents have the following meaning, unless specified otherwise:
Alkyl in the context of the invention is a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. The following may be mentioned by way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.
Alkandiyl in the context of the invention represents a straight-chain divalent alkyl radical having 1 to 4 carbon atoms. The following may be mentioned by way of example and by way of preference: methylene, ethane-1,2-diyl, propane-1,3-diyl and butane-1,4-diyl.
Cycloalkyl in the context of the invention is a monocyclic saturated alkyl radical having 3 to 7 or 3 to 6 carbon atoms. The following may be mentioned by way of example and by way of preference: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Carbocycle in the context of the invention represents a monocyclic saturated alkyl radical having 3 to 6 carbon atoms. The following may be mentioned by way of example and by way of preference: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Alkenyl in the context of the invention is a straight-chain or a branched alkenyl radical having 2 to 6 carbon atoms and one or two double bonds. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms and one double bond. The following may be mentioned by way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
Alkenyl in the context of the invention is a straight-chain or branched alkynyl radical having 2 to 6 carbon atoms and one triple bond. The following may be mentioned by way of example and by way of preference: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.
Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. The following may be mentioned by way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
Alkoxycarbonyl in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms and a carbonyl group attached to the oxygen. By way of example and for preference it includes the following: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
Monoalkylaminocarbonyl in the context of the invention represents an amino group which is attached via a carbonyl group and which has one straight-chain or branched alkyl substituent having 1 to 4 carbon atoms. The following may be mentioned by way of example and by way of preference: methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropyl-aminocarbonyl, n-butylaminocarbonyl and tert-butylaminocarbonyl.
Dialkylaminocarbonyl in the context of the invention represents an amino group which is attached via a carbonyl group and which has two identical or different straight-chain or branched alkyl substituents having 1 to 4 carbon atoms each. The following may be mentioned by way of example and by way of preference: N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-n-butyl-N-methylaminocarbonyl and N-tert-butyl-N-methylaminocarbonyl.
Heteroaryl in the context of the invention represents a mono- or optionally bicyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 10 ring atoms which contains up to three identical or different ring heteroatoms from the group consisting of N, O and S and is attached via a ring carbon atom or optionally via a ring nitrogen atom. The following may be mentioned by way of example: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, iso-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[3,4-b]pyridinyl. Preference is given to monocyclic 5- or 6-membered heteroaryl radicals having up to three ring heteroatoms from the group consisting of N, O and S such as furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl.
Halo=in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
An oxo group in the context of the invention is an oxygen atom attached via a double bond to a carbon atom.
In the formulae of the groups possible for R3 or R4, the end point of the line where there is a sign # or * does not represent a carbon atom or a CH2 group but forms part of the bond to the atom which is designated in each case and to which R3 and R4, respectively, are attached.
If radicals in the compounds according to the invention are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise. In the context of the present invention, all radicals which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred. Very particular preference is given to substitution by one substituent.
In the context of the present invention, preference is given to compounds of the formula (I) in which

    A represents a bond or —C(R6AR6B)—,

where

    R6A represents hydrogen,
    R6B represents hydrogen,
    R1 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C3-C6)-cycloalkyl,
    
        where (C1-C6)-alkyl and (C2-C6)-alkenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, oxo, hydroxy, trifluoromethyl, (C3-C6)-cycloalkyl, (C1-C4)-alkoxy, trifluoromethoxy and phenyl,
        
            in which (C3-C6)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of methyl, ethyl, oxo, hydroxy, methoxy, ethoxy and amino,
            and
            in which phenyl may be substituted by a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and aminocarbonyl,
        
        
        and
        where (C3-C6)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, methyl, ethyl, methoxy, ethoxy, hydroxy, amino and oxo,
    
    
    R2 represents phenyl or thienyl,
    
        where phenyl and thienyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy,
    
    
    R3 represents a group of the formula






    # represents the point of attachment to the nitrogen atom,
    L represents methylene,
    
        where methylene may be substituted by 1 or 2 methyl substituents,
    
    
    R7A represents hydrogen or methyl,
    R7B represents hydrogen or methyl,

or

    R7A and R7B together with the carbon atom to which they are attached form a cyclopropyl ring,
    R8 represents hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl,
    R9 represents hydroxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl,
    R4 represents phenyl,
    
        where phenyl is substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy,
    
    
    R5 represents hydrogen or methyl,

and to their salts, solvates and solvates of the salts.



Particular preference in the context of the present invention is given to compounds of the formula (I) in which

    A represents a bond or —C(R6AR6B)—,
    
        where
    
    
    R6A represents hydrogen,
    R6B represents hydrogen,
    R1 represents (C2-C4)-alkyl, (C2-C4)-alkenyl or cyclopropyl, where (C2-C4)-alkyl and (C2-C4)-alkenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, oxo, hydroxy and trifluoromethyl,
    R2 represents phenyl,
    
        where phenyl is substituted by a substituent selected from the group consisting of fluorine and chlorine,
    
    
    R3 represents a group of the formula






where

    # represents the point of attachment to the nitrogen atom,
    L represents methylene,
    R7A represents hydrogen or methyl,
    R7B represents hydrogen or methyl,

or

    R7A and R7B together with the carbon atom to which they are attached form a cyclopropyl ring,
    R8 represents hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl,
    R9 represents hydroxy, methoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl,
    R4 represents a group of the formula






where

    * represents the point of attachment to the group —C(R5)(AC(═O)NHR3)—,
    R10 represents hydrogen, chlorine, trifluoromethyl, trifluoromethoxy or methoxy,
    R11 represents hydrogen, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or methoxy,
    
        where at least one of the radicals R10 and R11 is different from hydrogen,
    
    
    R5 represents hydrogen or methyl,

and to their salts, solvates and solvates of the salts.



Preference in the context of the present invention is also given to compounds of the formula (I) in which R2 represents p-chlorophenyl, and to their salts, solvates and solvates of the salts.
Preference in the context of the present invention is also given to compounds of the formula (I) in which R1 represents 3,3,3-trifluoroprop-1-en-1-yl, and to their salts, solvates and solvates of the salts.
Preference in the context of the present invention is also given to compounds of the formula (I) in which R1 represents 3,3,3-trifluoropropyl, and to their salts, solvates and solvates of the salts.
Preference in the context of the present invention is also given to compounds of the formula (I) in which R1 represents 1,1,1-trifluoropropan-2-ol-3-yl, and to their salts, solvates and solvates of the salts.
Preference in the context of the present invention is also given to compounds of the formula (I) in which

    R1 represents (C2-C4)-alkyl or (C2-C4)-alkenyl,
    
        where (C2-C4)-alkyl and (C2-C4)-alkenyl are substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, oxo and trifluoromethyl

and to their salts, solvates and solvates of the salts.

    
    


Preference in the context of the present invention is also given to compounds of the formula (I) in which R1 represents cyclopropyl, and to their salts, solvates and solvates of the salts.
Preference in the context of the present invention is also given to compounds of the formula (I) in which
A represents C(R6AR6B)—,

    
    
        where
        R6A represents hydrogen,
        R6B represents hydrogen,

and to their salts, solvates and solvates of the salts.

    
    


Preference in the context of the present invention is also given to compounds of the formula (I) in which

    A represents C(R6AR6B)—,

where

    R6A represents hydrogen,
    R6B represents hydrogen,
    R3 represents a group of the formula






where

    # represents the point of attachment to the nitrogen atom,
    L represents methylene,
    R7A represents hydrogen or methyl,
    R7B represents hydrogen or methyl,

or

    R7A and R7B together with the carbon atom to which they are attached form a cyclopropyl ring,
    R8 represents hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl,
    R9 represents hydroxy, methoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl,

and to their salts, solvates and solvates of the salts.



Preference in the context of the present invention is also given to compounds of the formula (I) in which

    R4 represents a group of the formula






    
    
        where
        * represents the point of attachment to the group —C(R5)(AC(═O)NHR3)—,
        R10 represents hydrogen, trifluoromethoxy, chlorine, trifluoromethyl and methoxy,
        R11 represents hydrogen, trifluoromethoxy, fluorine, chlorine, trifluoromethyl and methoxy,
        where at least one of the radicals R10 and R11 is different from hydrogen,

and to their salts, solvates and solvates of the salts.

    
    


Preference in the context of the present invention is also given to the following compounds of the formula (I):

    ethyl 1-({[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylate (diastereomer mixture)
    1-({[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylic acid (diastereomer mixture)
    1-({[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylic acid (diastereomer 2)
    methyl N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alaninate (diastereomer mixture)
    N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alanine (diastereomer mixture)
    N3-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alaninamide (diastereomer 2)
    N3-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-beta-alaninamide
    methyl N-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate
    N-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine
    N2-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninamide
    methyl N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninate (diastereomer mixture)
    N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (diastereomer mixture)
    N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (diastereomer 2)
    N2-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (diastereomer mixture)
    N2-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (diastereomer 2)
    methyl N-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate
    N-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine
    N2-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninamide
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(1-hydroxy-2-methylpropan-2-yl)-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer 1)
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[2-(trifluoromethyl)phenyl]acetamide (diastereomer mixture)
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[2-(trifluoromethyl)phenyl]acetamide (diastereomer 2)
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer mixture)
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer 2)
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethoxy)phenyl]acetamide (diastereomer mixture)
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[2-(trifluoromethyl)phenyl]propanamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-methoxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-[2-(trifluoromethoxy)ethyl]-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer 2).


Particular preference in the context of the present invention is also given to the following compounds of the formula (I):

    N3-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alaninamide (diastereomer 2)
    N3-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-beta-alaninamide
    methyl-N-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate
    N-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine
    N2-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninamide
    N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (diastereomer mixture)
    N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (diastereomer 2)
    N2-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (diastereomer 2)
    N-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(1-hydroxy-2-methylpropan-2-yl)-2-[3-(trifluoromethyl)phenyl]-acetamide (diastereomer 1)
    2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer mixture)
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-methoxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide.


Preference in the context of the present invention is also given to the following compounds of the formula (I):

    methyl N-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate
    N-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine
    N2-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[2-(trifluoromethyl)phenyl]propanamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide
    (3S)-3-({[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl]amino)-N-(2-hydroxyethyl)-3-[2-(trifluoromethyl)phenyl]propanamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-methoxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide.


Particular preference in the context of the present invention is also given to the following compounds of the formula (I):

    N-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine
    N2-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[2-(trifluoromethyl)phenyl]propanamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide
    (3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-methoxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide.


The definitions of radicals indicated specifically in the respective combinations or preferred combinations of radicals are replaced as desired irrespective of the particular combinations indicated for the radicals also by definitions of radicals of other combinations.
Combinations of two or more of the abovementioned preferred ranges are very particularly preferred.
The invention furthermore provides a process for preparing the compounds of the formula (I) according to the invention, characterized in that
[A] a compound of the formula (II)




    
    
        in which R1 and R2 each have the meanings given above,
        is coupled in an inert solvent with activation of the carboxylic acid function with a compound of the formula (III)
    
    






    
    
        in which A, R3, R4 and R5 each have the meanings given above,

or

    
    


[B] a compound of the formula (IV)




    
    
        in which R1 and R2 each have the meanings given above,
        is reacted in an inert solvent in the presence of a base with a compound of the formula (V)
    
    






    
    
        in which A, R3, R4 and R5 each have the meanings given above,
        and
        X1 represents a leaving group, for example halogen, mesylate or tosylate,

or

    
    


[C] a compound of the formula (VI)




    
    
        in which A, R1, R2, R4 and R5 each have the meanings given above,
        is coupled in an inert solvent with activation of the carboxylic acid function with a compound of the formula (VII)

H2N—R3  (VII),

        in which R3 has the meaning given above,

and the resulting compounds of the formula (I) are optionally converted with the appropriate (i) solvents and/or (ii) acids or bases into their solvates, salts and/or solvates of the salts.

    
    


Inert solvents for the process steps (II)+(III)→(I) and (VI)+(VII)→(I) are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulphoxide, N,N-dimethylformamide, N,N′-dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). It is also possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile, dichloromethane, tetrahydrofuran, dimethylformamide or mixtures of these solvents.
Suitable condensing agents for the amide formation in process steps (II)+(III)→(I) and (VI)+(VII)→(I) are, for example, carbodiimides such as N,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC) or N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as N,N′-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline, or isobutyl chloroformate, propanephosphonic anhydride, diethyl cyanophosphonate, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) or O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with other additives such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu), and, as bases, alkali metal carbonates, e.g. sodium or potassium carbonate or hydrogen carbonate, or organic bases such as trialkylamines, e.g. triethylamine, N-methylmorpholine, N-methylpiperidine or N,N-diisopropylethylamine. Preferably EDC in combination with HOBt or TBTU in the presence of N,N-diisopropylethylamine is used.
The condensations (H)+(III)→(I) and (VI)+(VII)→(I) are generally carried out in a temperature range of from −20° C. to +60° C., preferably at from 0° C. to +40° C. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.
Suitable inert solvents for the process step (IV)+(V)→(I) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, dimethyl sulphoxide, N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or pyridine. It is also possible to use mixture of the solvents mentioned. Preference is given to using acetonitrile, acetone or dimethylformamide.
Suitable bases for the process step (IV)+(V)→(I) are the customary inorganic or organic bases. These preferably include alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO®). Preference is given to using potassium carbonate or caesium carbonate.
Here, the base is employed in an amount of from 1 to 5 mol, preferably in an amount from 1 to 2.5 mol, per mole of the compound of the formula (IV). The reaction is generally carried out in a temperature range of from 0° C. to +100° C., preferably at from +20° C. to +80° C. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar). The reaction is generally carried out at atmospheric pressure.
The preparation of the compounds according to the invention can be illustrated by the synthesis schemes below:




The compounds of the formulae (II), (IV) and (VI) are known from the literature (see, for example, WO 2007/134862), can be prepared analogously to processes known from the literature or as described in the present experimental part.
The compounds of the formulae (III), (V) and (VII) are commercially available, known from the literature or can be prepared analogously to processes known from the literature or as described in the present experimental part.
Further compounds according to the invention can also be prepared by converting functional groups of individual substituents, in particular those listed under R3, starting with the compounds of the formula (I) obtained by the above processes. These conversions can be carried out by customary methods known to the person skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalysed coupling reactions, eliminations, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carboxamides, and also the introduction and removal of temporary protective groups.
The compounds according to the invention possess valuable pharmacological properties and can be used for the prevention and/or treatment of various diseases and disease-induced states in humans and animals.
The compounds according to the invention are potent, selective dual V1a/V2 receptor antagonists, which inhibit vasopressin activity in vitro and in vivo. Furthermore, the compounds according to the invention have increased solubility in aqueous media.
The compounds according to the invention are therefore particularly suitable for the prophylaxis and/or treatment of cardiovascular diseases. In this connection, the following may for example and preferably be mentioned as target indications: acute and chronic heart failure, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischaemia, myocardial infarction, shock, arteriosclerosis, atrial and ventricular arrhythmias, transitory and ischaemic attacks, stroke, inflammatory cardiovascular diseases, peripheral and cardiac vascular diseases, peripheral circulation disorders, arterial pulmonary hypertension, spasms of the coronary arteries and peripheral arteries, thromboses, thromboembolic diseases, oedema formation such as for example pulmonary oedema, cerebral oedema, renal oedema or heart failure-related oedema, and restenoses for example after thrombolysis treatments, percutaneous-transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations.
In the sense of the present invention, the term heart failure also includes more specific or related disease forms such as right heart failure, left heart failure, global insufficiency, ischaemic cardiomyopathy, dilatative cardiomyopathy, congenital heart defects, heart valve defects, heart failure with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspidal stenosis, tricuspidal insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, heart muscle inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcohol-toxic cardiomyopathy, cardiac storage diseases, diastolic heart failure and systolic heart failure.
Furthermore, the compounds according to the invention are suitable for use as a diuretic for the treatment of oedemas and in electrolyte disorders, in particular in hypervolaemic and euvolaemic hyponatraemia.
The compounds according to the invention are also suitable for the prophylaxis and/or treatment of polycystic kidney disease (PCKD) and the syndrome of inadequate ADH secretion (SIADH).
In addition, the compounds according to the invention can be used for the prophylaxis and/or treatment of liver cirrhosis, ascites, diabetes mellitus and diabetic complications such as for example neuropathy and nephropathy, acute and chronic kidney failure and chronic renal insufficiency.
Further, the compounds according to the invention are suitable for the prophylaxis and/or treatment of central nervous disorders such as anxiety states and depression, of glaucoma and of cancer, in particular of pulmonary tumours.
Furthermore, the compounds according to the invention can be used for the prophylaxis and/or treatment of inflammatory diseases, asthmatic diseases, chronic-obstructive respiratory tract diseases (COPD), pain conditions, prostatic hypertrophy, incontinence, bladder inflammation, hyperactive bladder, diseases of the adrenals such as for example phaeochromocytoma and adrenal apoplexy, diseases of the intestine such as for example Crohn's disease and diarrhoea, or of menstrual disorders such as for example dysmenorrhoea or of endometriosis.
A further object of the present invention is the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of the diseases mentioned above.
A further object of the present invention is the compounds according to the invention for use in a method for the treatment and/or prophylaxis of acute and chronic heart failure, hypervolaemic and euvolaemic hyponatraemia, liver cirrhosis, ascites, oedemas, and the syndrome of inadequate ADH secretion (SIADH).
A further object of the present invention is the use of the compounds according to the invention for the production of a medicament for the treatment and/or prophylaxis of diseases, in particular of the diseases mentioned above.
A further object of the present invention is a method for the treatment and/or prophylaxis of diseases, in particular of the diseases mentioned above, with the use of an effective quantity of at least one of the compounds according to the invention.
The compounds according to the invention can be used alone or if necessary in combination with other active substances. A further object of the present invention are medicaments which contain at least one of the compounds according to the invention and one or more other active substances, in particular for the treatment and/or prophylaxis of the diseases mentioned above. As combination active substances suitable for this, the following may for example and preferably be mentioned:

    
    
        organic nitrates and NO donors, such as for example sodium nitroprusside, nitroglycerine, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhalational NO;
        diuretics, in particular loop diuretics and thiazides and thiazide-like diuretics;
        positive-inotropically active compounds, such as for example cardiac glycosides (digoxin), and beta-adrenergic and dopaminergic agonists such as isoproterenol, adrenalin, noradrenalin, dopamine and dobutamine;
        compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as for example inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and/or 5, in particular PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil, and PDE 3 inhibitors such as aminone and milrinone;
        natriuretic peptides such as for example “atrial natriuretic peptide” (ANP, anaritide), “B-type natriuretic peptide” or “brain natriuretic peptide” (BNP, nesiritide), “C-type natriuretic peptide” (CNP) and urodilatin;
        calcium sensitizers, such as for example and preferably levosimendan;
        NO- and haem-independent activators of guanylate cyclase, such as in particular cinaciguat and also the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
        NO-independent, but haem-dependent stimulators of guanylate cyclase, such as in particular riociguat and also the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
        inhibitors of human neutrophil elastase (HNE), such as for example sivelestat or DX-890 (reltran);
        compounds inhibiting the signal transduction cascade, such as for example tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib;
        compounds influencing the energy metabolism of the heart, such as for example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;
        agents with antithrombotic action, for example and preferably from the group of the thrombocyte aggregation inhibitors, anticoagulants or profibrinolytic substances;
        blood pressure-lowering active substances, for example and preferably from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and rho-kinase inhibitors; and/or
        active substances modifying the fat metabolism, for example and preferably from the group of the thyroid receptor agonists, cholesterol synthesis inhibitors such as for example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein(a) antagonists.
    
    


In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as for example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorothalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorophenamide, methazolamide, glycerine, isosorbide, mannitol, amiloride or triamterene.
Agents with antithrombotic action are understood preferably to mean compounds from the group of the thrombocyte aggregation inhibitors, anticoagulants or profibrinolytic substances.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombocyte aggregation inhibitor, such as for example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as for example and preferably ximela-gatran, melagatran, bivalirudin or clexane.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist, such as for example and preferably tirofiban or abciximab.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as for example and preferably riva-roxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, such as for example and preferably coumarin.
Blood pressure-lowering agents are understood preferably to mean compounds from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and diuretics.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as for example and preferably nifedipine, amlodipine, verapamil or diltiazem.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as for example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor, such as for example and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vasopeptidase inhibitor or inhibitor of neutral endopeptidase (NEP).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as for example and preferably bosentan, darusentan, ambrisentan or sitaxsentan.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a renin inhibitor, such as for example and preferably aliskiren, SPP-600 or SPP-800.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1 receptor blocker, such as for example and preferably prazosin.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta-receptor blocker, such as for example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, meti-pranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as for example and preferably spironolactone, eplerenone, canrenone or potassium canrenoate.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a rho-kinase inhibitor, such as for example and preferably fasu-dil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
Fat metabolism-modifying agents are understood preferably to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as for example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP-vaccine (CETi-1).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as for example and preferably D-thyroxine, 3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of the statins, such as for example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as for example and preferably BMS-188494 or TAK-475.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as for example and preferably avasi-mibe, melinamide, pactimibe, eflucimibe or SMP-797.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor, such as for example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as for example and preferably pio-glitazone or rosiglitazone.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as for example and preferably GW-501516 or BAY 68-5042.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as for example and preferably ezetimibe, tiqueside or pamaqueside.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as for example and preferably orlistat.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as for example and preferably cholestyramine, colestipol, colesolvam, cholestagel or colestimide.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as for example and preferably ASBT(=IBAT) inhibitors such as for example AZD-7806, S-8921, AK-105, BAR1-1741, SC-435 or SC-635.
In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein(a) antagonist, such as for example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
A further object of the present invention are medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and the use thereof for the aforesaid purposes.
The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, such as for example by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic routes or as an implant or stent.
For these administration routes, the compounds according to the invention can be administered in suitable administration forms.
For oral administration, administration forms which function according to the state of the art, releasing the compounds according to the invention rapidly and/or in a modified manner, which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, such as for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed dissolution or insoluble coatings, which control the release of the compound according to the invention), tablets rapidly disintegrating in the oral cavity or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions are suitable.
Parenteral administration can be effected by omitting an absorption step (e.g. intravenous, intra-arterial, intracardial, intraspinal or intralumbar administration) or by involving absorption (e.g. intra-muscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal administration). Suitable administration forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
For the other administration routes, for example inhalation formulations (including powder inhalers and nebulizers), nasal drops, solutions or sprays, tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, aural or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shakable mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, dusting powders, implants or stents are suitable.
Oral or parenteral administration, in particular oral and intravenous administration, are preferred.
The compounds according to the invention can be converted into the stated administration forms. This can be effected in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These auxiliaries include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as for example ascorbic acid), colorants (e.g. inorganic pigments such as for example iron oxides) and flavour and/or odour correctors.
In general, to achieve effective results in parenteral administration it has been found to be advantageous to administer quantities of about 0.01 to 1 mg/kg body weight. In oral administration, the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and quite especially preferably 0.1 to 10 mg/kg body weight.
Nonetheless it can sometimes be necessary to deviate from said quantities, namely depending on body weight, administration route, individual response to the active substance, nature of the preparation and time or interval at which the administration takes place. Thus in some cases it can be sufficient to manage with less than the aforesaid minimum quantity, while in other cases the stated upper limit must be exceeded. In the event of administration of larger quantities, it may be advisable to divide these into several individual administrations throughout the day.
The following practical examples illustrate the invention. The invention is not limited to the examples.
Unless otherwise stated, the percentages stated in the following tests and examples are percent by weight, parts are parts by weight, and solvent ratios, dilution ratios and concentration information about liquid/liquid solutions are each based on volume.


A. EXAMPLES
Abbreviations


    BOC tert-butoxycarbonyl
    CI chemical ionization (in MS)
    DCI direct chemical ionization (in MS)
    DME 1,2-dimethoxyethane
    DMF N,N′-dimethylformamide
    DMSO dimethyl sulphoxide
    EDC N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
    eq. equivalent(s)
    ESI electrospray ionization (in MS)
    GC/MS gas chromatography-coupled mass spectrometry
    sat. saturated
    h hour(s)
    HOBt 1-hydroxy-1H-benzotriazole hydrate
    HPLC high pressure, high performance liquid chromatography
    HV high vacuum
    conc. concentrated
    LC/MS liquid chromatography-coupled mass spectrometry
    LDA lithium diisopropylamide
    LiHMDS lithium hexamethyldisilazane
    min minute(s)
    MS mass spectrometry
    MTBE methyl tert-butyl ether
    NMR nuclear magnetic resonance spectrometry
    rac racemic/racemate
    Rf retention factor (in thin-layer chromatography on silica gel)
    RT room temperature
    Rt retention time (in HPLC)
    THF Tetrahydrofuran
    TMOF trimethyl orthoformate
    UV ultraviolet spectrometry
    v/v ratio by volume (of a solution)

LC/MS, HPLC and GC/MS Methods:



Method 1: MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20 mm×4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A→0.1 min 90% A→3.0 min 5% A→4.0 min 5% A→4.01 min 90% A; flow rate: 2 ml/min; oven: 50° C.; UV detection: 210 nm.
Method 2: MS instrument type: Waters (Micromass) Quattro Micro; HPLC instrument type: Agilent 1100 Serie; column: Thermo Hypersil GOLD 3μ 20×4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100% A→3.0 min 10% A→4.0 min 10% A→4.01 min 100% A (flow rate 2.5 ml)→5.00 min 100% A; oven: 50° C.; flow rate: 2 ml/min; UV detection: 210 nm.
Method 3: Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9μ 50×1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A→0.1 min 90% A→1.5 min 10% A→2.2 min 10% A oven: 50° C.; flow rate: 0.33 ml/min; UV detection: 210 nm.
Method 4: MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series; UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A→2.5 min 30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min, 2.5 min/3.0 min/4.5 min. 2 ml/min; oven: 50° C.; UV detection: 210 nm.
Method 5: Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8μ 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99% strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 210-400 nm.
Method 6 (preparative HPLC): column: Grom-Sil 1200DS-4HE, 10 μm, SNr. 3331, 250 mm×30 mm mobile phase A: formic acid 0.1% in water, mobile phase B: acetonitrile; flow rate: 50 ml/min program: 0-6 min: 10% B; 6-27 min gradient to 95% B; 27-38 min: 95% B; 38-45 min: 10% B.
Method 7 (preparative HPLC): column: Reprosil C18, 10 μm, 250 mm×30 mm mobile phase A: formic acid 0.1% in water, mobile phase B: methanol; flow rate: 50 ml/min program: 0 to 4.25 min: 60% A/40% B; 4.25 to 4.50 min gradient to 60% B; 4.50 min to 17 min gradient to 100% B; 17 min to 19.50 min 100% B; 19.50 min to 19.75 min gradient to 40% B; 19.75 to 22 min (end): 60% A/40% B.
Method 8 (preparative HPLC): column: Reprosil C18, 10 μm, 250 mm×30 mm mobile phase A: formic acid 0.1% in water, mobile phase B: acetonitrile; flow rate: 50 ml/min program: 0 to 6 min: 90% A/10% B; 6 min to 27 min: gradient to 95% B; 27 min to 38 min 95% B; 38 min to 39 min gradient to 10% B; 39 min to 43 min (end): 60% A/40% B.
Method 9 (preparative HPLC): column: Grom-Sil 1200DS-4HE, 10 μm, SNo. 3331, 250 mm×30 mm mobile phase A: formic acid 0.1% in water, mobile phase B: acetonitrile; flow rate: 50 ml/min program: 0-6 min: 5% B; 6-34 min: gradient to 95% B; 34-38 min: 95% B; 38-45 min: 5% B.
Method 10 (chiral preparative HPLC): chiral stationary silica gel phase based on the selector poly-(N-methacryloyl-D-leucine-dicyclopropylmethylamide); column: 670 mm×40 mm; mobile phase: 100% ethyl acetate; flow rate: 80 ml/min, temperature: 24° C.; UV detector 260 nM.
Method 11 (chiral analytical HPLC): chiral stationary silica gel phase based on the selector poly-(N-methacryloyl-D-leucine-dicyclopropylmethylamide); column: 250 mm×4.6 mm, mobile phase ethyl acetate 100%, flow rate: 2 ml/min, temperature: 24° C.; UV detector 265 nM.
Method 12 (chiral preparative HPLC): chiral stationary vinyl silica gel phase based on the selector poly(N-methacryloyl-L-leucine-tert-butylamide); column: 670 mm×40 mm; mobile phase: isohexane/ethyl acetate 2:1; flow rate: 80 ml/min., temperature: 24° C.; UV detector 265 nM.
Method 13 (chiral analytical HPLC): chiral stationary vinyl silica gel phase based on the selector poly(N-methacryloyl-D-leucine-tert-butylamide); column: 250 mm×4.6 mm, mobile phase: isohexane/ethyl acetate 2:1; flow rate 1 ml/min, temperature 24° C.; UV-Detector 265 nM.
Method 14 (chiral preparative HPLC): stationary phase Daicel Chiralpak AD-H, 10 nm, column: 250 mm×20 mm; temperature: RT; UV detection: 230 nm; flow rate: 20 ml/min

    
    
        Method 14a: mobile phase: isohexane/isopropanol 70:30 (v/v).
        Method 14b: mobile phase: isohexane/isopropanol 50:50 (v/v).
    
    


Method 15 (chiral analytical HPLC): stationary phase Daicel Chiralpak AD-H, 5 nm, column: 250 mm×4.6 mm; temperature: 30° C.; UV detection: 230 nm; flow rate: 1.0 ml/min Various mobile phases:

    
    
        Method 15a: mobile phase: isohexane/isopropanol 70:30 (v/v).
        Method 15b: mobile phase: isohexane/isopropanol 50:50 (v/v).
    
    


Starting Materials and Intermediates
Example 1A
Ethyl N-({2-[(4-chlorophenyl)carbonyl]hydrazinyl}carbonyl)glycinate




A suspension of 12.95 g (75.9 mmol) of 4-chlorobenzhydrazide in 50 ml of dry THF was initially charged at 50° C., and a solution of 10.0 g (77.5 mmol) of ethyl 2-isocyanatoacetate in 100 ml of dry THF was added dropwise. Initially, a solution was formed, and then a precipitate. After the addition had ended, the mixture was stirred at 50° C. for a further 2 h and then allowed to stand overnight. The crystals were isolated by filtration, washed with a little diethyl ether and dried under HV. This gave 21.43 g (89% of theory) of the title compound.
LC/MS [Method 1]: Rt=1.13 min; m/z=300 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ=10.29 (s, 1H), 8.21 (s, 1H), 7.91 (d, 2H), 7.57 (d, 2H), 6.88 (br.s, 1H), 4.09 (q, 2H), 3.77 (d, 2H), 1.19 (t, 3H)
Example 2A
[3-(4-Chlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]acetic acid




91 ml of a 3N aqueous sodium hydroxide solution were added to 21.43 g (67.93 mmol) of the compound of Example 1A, and the mixture was heated at reflux overnight. After cooling to RT, the mixture was adjusted to pH 1 by slow addition of about 20% strength hydrochloric acid. The precipitated solid was isolated by filtration, washed with water and dried under reduced pressure at 60° C. Yield: 17.55 g (90% of theory, about 88% pure).
LC/MS [Method 1]: Rt=0.94 min; m/z=254 (M+H)+
1H NMR (DMSO-d6, 400 MHz): δ=13.25 (br.s, 1H), 12.09 (s, 1H), 7.65-7.56 (m, 4H), 4.45 (s, 2H).
Example 3A
5-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (or as hydrate: 5-(4-chlorophenyl)-4-(3,3,3-trifluoro-2,2-dihydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one)




Under argon, 5 g (16.36 mmol) of the compound of Example 2A were dissolved in 200 ml of pyridine, and 17.18 g (81.8 mmol) of trifluoroacetic anhydride were then added. During the addition, the temperature increased to about 35° C. After 30 min, the pyridine was removed on a rotary evaporator and the residue was diluted with 1.5 l of 0.5N hydrochloric acid. This mixture was heated to 70° C. and then filtered whilst still hot. The solid was washed with a little water. The entire filtrate was extracted three times with ethyl acetate. The combined organic phases were washed with water, then with a saturated aqueous sodium bicarbonate solution, then with a saturated aqueous sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dried under HV. Yield: 3.56 g (68% of theory) of the title compound as a hydrate.
LC/MS [Method 1]: Rt=1.51 min; m/z=306 (M+H)+ and 324 (M+H)+ (ketone or hydrate)
1H NMR (DMSO-d6, 400 MHz): δ=12.44 (s, 1H), 7.72 (d, 2H), 7.68 (br.s, 2H), 7.61 (d, 2H), 3.98 (s, 2H).
Example 4A
5-(4-Chlorophenyl)-4-(3,3,3-trifluoro-2-hydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one




3.56 g (11 mmol) of the compound of Example 3A were dissolved in 100 ml of methanol, and 3.75 g (99 mmol) of sodium borohydride were added with ice cooling (evolution of gas). After 1.5 h, 200 ml of 1M hydrochloric acid were added slowly. The methanol was removed on a rotary evaporator, and the residue was diluted with 500 ml of water and extracted three times with ethyl acetate. The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dried under HV. This gave 3.04 g (90% of theory) of the title compound.
LC/MS [Method 2]: Rt=1.80 min; m/z=308 (M+H)+.
1H NMR (DMSO-d6, 400 MHz): δ=12.11 (s, 1H), 7.75 (d, 2H), 7.62 (d, 2H), 6.85 (d, 1H), 4.34-4.23 (m, 1H), 3.92 (dd, 1H), 3.77 (dd, 1H).
Example 5A
Methyl[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoro-2-hydroxypropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate




3.04 g (9.9 mmol) of the compound of Example 4A were dissolved in 100 ml of acetonitrile, and 1.07 g (9.9 mmol) of methyl chloroacetate, 2.73 g (19.8 mmol) of potassium carbonate and a small spatula tip of potassium iodide were added. The reaction mixture was heated at reflux for 1 h, allowed to cool to RT and filtered. The filtrate was freed from the volatile components on a rotary evaporator and the residue was dried under HV. Yield: 3.70 g (89% of theory) of the title compound in a purity of about 90%.
LC/MS [Method 3]: Rt=1.10 min; m/z=380 (M+H)+.
1H NMR (DMSO-d6, 400 MHz): δ=7.78 (d, 2H), 7.64 (d, 2H), 6.91 (d, 1H), 4.72 (s, 2H), 4.16-4.35 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.70 (s, 3H).
The racemic compound of Example 5A was, as described in WO 2007/134862, separated by preparative HPLC on a chiral phase into the enantiomers Example 6A and Example 7A.
Column: chiral silica gel phase based on the selector poly(N-methacryloyl-L-isoleucine-3-pentylamide, 430 mm×40 mm; mobile phase: stepped gradient isohexane/ethyl acetate 1:1 (v/v)→ethyl acetate→isohexane/ethyl acetate 1:1 (v/v); flow rate: 50 ml/min; temperature: 24° C.; UV detection: 260 nm.
In this manner, 3.6 g of the racemic compound of Example 5A (dissolved in 27 ml of ethyl acetate and 27 ml of isohexane and separated in three portions on the column) gave 1.6 g of enantiomer 1 (Example 6A), which eluted first, and 1.6 g of enantiomer 2 (Example 7A), which eluted later.
Example 6A
Methyl{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate (enantiomer 1)




First-eluting enantiomer from the racemate separation of Example 5A.
Rt=3.21 min [column: chiral silica gel phase based on the selector poly(N-methacryloyl-L-isoleucine-3-pentylamide, 250 mm×4.6 mm; mobile phase: isohexane/ethyl acetate 1:1; flow rate: 1 ml/min; UV detection: 260 nm].
Example 7A
Methyl{3-(4-chlorophenyl)-5-oxo-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate (enantiomer 2)




Last-eluting enantiomer from the racemate separation of Example 5A.
Rt=4.48 min [column: chiral silica gel phase based on the selector poly(N-methacryloyl-L-isoleucine-3-pentylamide, 250 mm×4.6 mm; mobile phase: isohexane/ethyl acetate 1:1; flow rate: 1 ml/min; UV detection: 260 nm].
Example 8A
{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetic acid




The enantiomerically pure ester of Example 6A (1.6 g, 4.21 mmol) was dissolved in 77 ml of methanol, and 17 ml of a 1M solution of lithium hydroxide in water were added. The mixture was stirred at RT for 1 h and then concentrated on a rotary evaporator. The residue was diluted with 100 ml of water and acidified to pH 1-2 with 1N of hydrochloric acid. The precipitated product was filtered off, washed successively with water and cyclohexane and sucked dry. Further drying under HV gave the title compound (1.1 g, 71% of theory).
[α]D′=+3.4° (methanol, c=0.37 g/100 ml)
LC/MS [Method 1]: Rt=1.51 min; m/z=366 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H), 4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s, 1H).
Example 9A
{3-(4-Chlorophenyl)-5-oxo-4-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetic acid




Analogously to Example 8A, Example 7A gave the title compound.
[α]D′=−4.6° (methanol, c=0.44 g/100 ml)
LC/MS [Method 1]: Rt=1.53 min; m/z=366 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ=3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H), 4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s, 1H).
Example 10A
Methyl{3-(4-chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetate




At RT, 280 mg (0.74 mmol) of the compound of Example 7A were initially charged together with 108 mg (0.89 mmol) of 4-dimethylaminopyridine in 5.3 ml of pyridine, 0.31 ml of trifluoromethanesulphonic anhydride (1.84 mmol) was added in portions and the mixture was stirred for 12 h. The pyridine was removed on a rotary evaporator. The residue was taken up in acetonitrile and 1N hydrochloric acid and purified by preparative HLPC [Method 9]. This gave 230 mg (86% of theory) of the title compound.
LC/MS [Method 4]: Rt=1.14 min; m/z=362 (M+H)+
1H-NMR (400 MHz, DMSO-d6): 6 [ppm]=3.72 (s, 3H), 4.78 (s, 2H), 6.85 (dd, 1H), 7.18 (d, 1H), 7.68 (s, 4H).
Example 11A
{3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetic acid




260 mg (0.72 mmol) of the compound of Example 10A were dissolved in 5 ml of methanol, and 2.87 ml (2.87 mmol) of a 1M aqueous lithium hydroxide solution were added. The mixture was stirred at RT for 1 h and then acidified with 1N hydrochloric acid and diluted with DMSO. The entire solution was purified by preparative HLPC [Method 9]. This gave 215 mg (86% of theory) of the title compound.
LC/MS [Method 4]: Rt=1.03 min; m/z=348 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=4.64 (s, 2H), 6.79-6.92 (m, 1H), 7.19 (dd, 1H), 7.68 (s, 4H), 13.31 (br. s, 1H).
Example 12A
2-[(5-Chloro-2-thienyl)carbonyl]-N-(2-methoxyethyl)hydrazinecarboxamide




At 50° C., 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide were finely suspended in 30 ml of dry THF. 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane dissolved in 30 ml of THF were then added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator, and diethyl ether was added to the residue. The crystals were filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 4.87 g (100% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ=3.14-3.21 (m, 2H), 3.28-3.36 (m, 5H), 6.52 (br. s, 1H), 7.22 (d, 1H), 7.70 (d, 1H), 7.97 (s, 1H), 10.24 (s, 1H).
Example 13A
5-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one




4.85 g (17.46) mmol of the compound of Example 12A were dissolved in 17 ml (52.39 mmol) of 3M aqueous sodium hydroxide solution and heated under reflux for 168 h. After 16, 40, 64 and 88 h, in each case 1.05 g (26.19 mmol, 104.76 mmol in total) of solid sodium hydroxide were added. Using 1M hydrochloric acid, the mixture was adjusted to pH 10, and the mixture was extracted twice with in each case 30 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered, freed from the solvent on a rotary evaporator and dried under high vacuum. This gave 2.44 g (54% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ=3.20 (s, 3H), 3.53 (t, 2H), 3.92 (t, 2H), 7.24 (d, 1H), 7.51 (d, 1H), 12.04 (s, 1H).
Example 14A
Ethyl[3-(5-chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetate




2.4 g (9.24 mmol) of the compound of Example 13A and 2.55 g (18.48 mmol) of potassium carbonate were suspended in 48 ml of acetonitrile. 1.08 ml (10.17 mmol) of ethyl chloroacetate were then added, and the mixture was heated under reflux at 80° C. for 4.5 h. Another 113 mg (0.92 mmol) of ethyl chloroacetate were added, and the mixture was stirred at 80° C. for 2 h. The suspension was filtered through a layer of silica gel, the silica gel was washed with ethyl acetate and the filtrate was evaporated on a rotary evaporator and dried under HV. This gave 3.24 g (100% of theory) of the title compound.
LC/MS [Method 22]: Rt=2.42 min; m/z=346 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ=1.21 (t, 3H), 3.30 (s, 3H), 3.55 (t, 2H), 3.99 (t, 2H), 4.15 (q, 2H), 4.65 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H).
Example 15A
[3-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid




3.2 g (9.25 mmol) of the compound of Example 14A were dissolved in 28 ml of methanol. 2.82 ml of 20% strength aqueous potassium hydroxide solution were then added. The mixture was stirred at RT for 2 h. On a rotary evaporator, the proportion of methanol was reduced by half. The mixture was then diluted with water and extracted once with 15 ml of ethyl acetate. The aqueous phase was acidified with 920 μl of concentrated hydrochloric acid and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated on a rotary evaporator. Drying under high vacuum gave 2.34 g (80% of theory) of the title compound.
LC/MS [Method 22]: Rt=2.05 min; m/z=318 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ=3.20 (s, 3H), 3.55 (t, 2H), 3.99 (t, 2H), 4.53 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H), 13.14 (br. s, 1H).
Example 16A
(2R)-2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoic acid




250 mg of the compound of Example 8A (0.68 mmol) of and 92 mg (0.68 mmol) of HOBt were initially charged in 5 ml of DMF, and 131 mg (0.68 mmol) of EDC were added. The mixture was stirred at RT for 20 min and then added dropwise to a solution of 221 mg (0.82 mmol) of (2R)-2-amino-2-[3-(trifluoromethyl)phenyl]propionic acid hydrochloride and 119 μl (0.68 mmol) of N,N-diisopropylethylamine in 2 ml of DMF. The reaction mixture was stirred at RT for 20 min, 1 ml of 1N hydrochloric acid was then added and the product was purified by preparative HPLC (Method 10). The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under HV. This gave 260 mg (65% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.23 min; MS [ESIpos]: m/z=581 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.85 (s, 3H), 3.76-3.88 (m, 1H), 3.90-4.01 (m, 1H), 4.26 (br. s., 1H), 4.51-4.67 (m, 2H), 6.92 (d, 1H), 7.55-7.71 (m, 4H), 7.71-7.83 (m, 4H), 8.80 (s, 1H), 13.10 (s, 1H).
Example 17A
Ethyl 1-({[(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylate




A mixture of 500 mg (1.57 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)-phenyl]acetic acid, 243 mg (1.88 mmol) of ethyl 1-aminocyclopropanecarboxylate, 450 mg (2.35 mmol) of EDC and 317 mg (2.35 mmol) of HOBt in 10 ml of DMF was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed twice with 1N hydrochloric acid and once with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and then freed from the solvent on a rotary evaporator. The residue was dried under high vacuum. This gave 650 mg (96% of theory) of the title compound.
LC-MS [Method 1]: Rt=2.11 min; MS [ESIpos]: m/z=431 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.92 (t, 3H), 0.95-1.04 (m, 2H), 1.24-1.33 (m, 2H), 1.37 (s, 9H), 3.89 (q, 2H), 5.23 (d, 1H), 7.50 (br. d, 1H), 7.59 (t, 1H), 7.66 (d, 1H), 7.73 (d, 1H), 7.80 (s, 1H), 8.91 (s, 1H).
Example 18A
Methyl N-{[(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninate




450 mg (2.35 mmol) of EDC were added to a mixture of 500 mg (1.57 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 317 mg (2.35 mmol) of HOBt in 10 ml of DMF, and the mixture was stirred at RT for 20 min. 313 mg (2.04 mmol) of methyl 2-methylalaninate hydrochloride and 382 μl (2.19 mmol) of N,N′-diisopropylethylamine were added and the mixture was stirred overnight. For purification, the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 502 mg (77% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.28 min; MS [ESIpos]: m/z=319 (M+H−BOC)+; [ESIneg]: m/z=417 (M−H)−.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.26 (s, 3H), 1.38 (d, 12H), 3.44 (s, 3H), 5.31 (d, 1H), 7.45 (br. d, 1H), 7.56-7.62 (m, 1H), 7.63-7.71 (m, 2H), 7.75 (br. s, 1H), 8.61-8.69 (m, 1H).
Example 19A
Methyl N-{[(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alaninate




Analogously to Example 18A, 250 mg (0.78 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 142 mg (1.02 mmol) of methyl beta-alaninate hydrochloride gave 256 mg (81% of theory) of the title compound.
LC-MS [Method 1]: Rt=1.90 min; MS [ESIpos]: m/z=405 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.37 (s, 9H), 2.42 (t, 2H), 3.20-3.33 (m, 2H), 3.51 (s, 3H), 5.23 (d, 1H), 7.51 (br. d, 1H), 7.54-7.60 (m, 1H), 7.61-7.71 (m, 2H), 7.76 (br. s, 1H), 8.36 (t, 1H).
Example 20A
tert-Butyl{2-[(3-amino-3-oxopropyl)amino]-2-oxo-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (racemate)




360 mg (1.88 mmol) of EDC were added to a mixture of 400 mg (1.25 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 254 mg (1.88 mmol) of HOBt in 12 ml of DMF, and the mixture was stirred at RT for 30 min 234 mg (1.88 mmol) of beta-alaninamide hydrochloride and 436 μl (2.50 mmol) of N,N′-diisopropylethylamine were added, and the mixture was stirred for another 1 h. The mixture was diluted with ethyl acetate and washed four times with water. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dried under high vacuum. This gave 446 mg (91% of theory) of the title compound.
LC-MS [Method 1]: Rt=1.56 min; MS [ESIpos]: m/z=390 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.37 (s, 9H), 2.11-2.26 (m, 2H), 3.15-3.28 (m, 2H), 5.25 (d, 1H), 6.81 (br. s., 1H), 7.29 (br. s., 1H), 7.50 (d, 1H), 7.53-7.60 (m, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.77 (s, 1H), 8.30 (t, 1H).
By chromatography on a chiral phase [Method 14a], the title compound was separated into its enantiomers: see Examples 21A and 22A.
Example 21A
tert-Butyl{2-[(3-amino-3-oxopropyl)amino]-2-oxo-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (enantiomer 1)




First-eluting enantiomer (205 mg) from the chromatographic enantiomer separation of the compound of Example 20A according to Method 14a.
Chiral analytical HPLC [Method 15b]: Rt=3.29 min
Example 22A
tert-Butyl{2-[(3-amino-3-oxopropyl)amino]-2-oxo-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate (enantiomer 2)




Last-eluting enantiomer (208 mg) from the chromatographic enantiomer separation of the compound of Example 20A according to Method 14a.
Chiral analytical HPLC [Method 15b]: Rt=4.15 min
Example 23A
tert-Butyl{2-[(1-amino-2-methyl-1-oxopropan-2-yl)amino]-2-oxo-1-[3-(trifluoromethyl)phenyl]-ethyl}carbamate




Analogously to Example 18A, 222 mg (0.69 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 115 mg (0.77 mmol) of 2-methylalaninamide hydrochloride gave 237 mg (85% of theory) of the title compound.
LC-MS [Method 4]: Rt=2.04 min; MS [ESIpos]: m/z=404 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (s, 3H), 1.33 (s, 3H), 1.38 (s, 9H), 5.23 (d, 1H), 6.96 (br. s, 1H), 6.99 (br. s, 1H), 7.50-7.61 (m, 2H), 7.64 (d, 1H), 7.69 (d, 1H), 7.77 (s, 1H), 8.28 (br. s., 1H).
Example 24A
tert-Butyl{2-[(1-amino-2-methyl-1-oxopropan-2-yl)amino]-2-oxo-1-[2-(trifluoromethyl)phenyl]-ethyl}carbamate




Analogously to Example 18A, 250 mg (0.78 mmol) of [(tert-butoxycarbonyl)amino][2-(trifluoromethyl)phenyl]acetic acid and 119 mg (0.86 mmol) of 2-methylalaninamide hydrochloride gave 220 mg (70% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.07 min; MS [ESIpos]: m/z=404 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.38 (br. s., 9H), 1.39 (br. s., 3H), 1.41 (s, 3H), 5.36 (d, 1H), 7.12 (s, 1H), 7.22 (br. s., 1H), 7.50 (t, 1H), 7.57 (d, 1H), 7.63-7.73 (m, 2H), 7.90 (d, 1H), 8.04 (s, 1H).
Example 25A
tert-Butyl{2-[(1-amino-2-methyl-1-oxopropan-2-yl)amino]-1-(2-chlorophenyl)-2-oxoethyl}carbamate




Analogously to Example 18A, 250 mg (0.88 mmol) of [(tert-butoxycarbonyl)amino](2-chlorophenyl)acetic acid and 133 mg (0.96 mmol) of 2-methylalaninamide hydrochloride gave 263 mg (81% of theory) of the title compound.
LC-MS [Method 5]: Rt=0.81 min; MS [ESIpos]: m/z=370 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.38 (br. s., 3H), 1.39 (br. s., 9H), 1.41 (s, 3H), 5.40 (d, 1H), 7.08 (br. s., 1H), 7.11 (br. s., 1H), 7.29-7.35 (m, 2H), 7.37-7.48 (m, 2H), 7.69 (d, 1H), 8.06 (s, 1H).
Example 26A
[(tert-Butoxycarbonyl)amino](2,3-dichlorophenyl)acetic acid




A solution of 500 mg (2.27 mmol) of amino(2,3-dichlorophenyl)acetic acid in 25 ml of 5% strength aqueous sodium bicarbonate solution was diluted with 25 ml of dioxane, and 532 ml (2.32 mmol) of di-tert-butyl dicarbonate were added. The reaction mixture was stirred at RT overnight. For work-up, 150 ml of 1N hydrochloric acid were added, and the product was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dried under high vacuum. This gave 750 mg (quant. yield) of the title compound.
LC-MS [Method 5]: Rt=1.00 min; MS [ESIpos]: m/z=320 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.38 (s, 9H), 5.62 (d, 1H), 7.35-7.45 (m, 2H), 7.61 (dd, 1H), 7.83 (d, 1H), 13.12 (br. s., 1H).
Example 27A
tert-Butyl{2-[(1-amino-2-methyl-1-oxopropan-2-yl)amino]-1-(2,3-dichlorophenyl)-2-oxoethyl}carbamate




Analogously to Example 18A, 250 mg (0.78 mmol) of the compound of Example 26A and 119 mg (0.86 mmol) of 2-methylalaninamide hydrochloride gave 250 mg (77% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.11 min; MS [ESIpos]: m/z=404 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.34-1.43 (m, 15H), 5.45 (d, 1H), 7.05 (br. s., 1H), 7.10 (br. s., 1H), 7.32-7.39 (m, 2H), 7.56-7.61 (m, 1H), 7.81 (d, 1H), 8.15 (s, 1H).
Example 28A
Methyl N-{(3S)-3-[(cert-butoxycarbonyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate




Analogously to Example 18A, 125 mg (0.38 mmol) of (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoic acid and 86 mg (0.56 mmol) of methyl 2-methylalaninate hydrochloride gave 130 mg (80% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.26 min; MS [ESIpos]: m/z=433 (M+H)+.
Example 29A
tert-Butyl{2-[(1-hydroxy-2-methylpropan-2-yl)amino]-2-oxo-1-[3-(trifluoromethyl)phenyl]ethyl}-carbamate (racemate)




360 mg (1.88 mmol) of EDC were added to a mixture of 400 mg (1.25 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 254 mg (1.88 mmol) of HOBt in 10 ml of DMF, and the mixture was stirred at RT for 20 min. The resulting solution was added dropwise to a solution of 168 mg (1.88 mmol) of 2-amino-2-methyl-1-propanol in 2 ml of DMF. The reaction mixture was stirred at RT for 20 min. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 364 mg (74% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.21 min; MS [ESIpos]: m/z=391 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.13 (s, 3H), 1.14 (s, 3H), 1.38 (s, 9H), 3.26-3.32 (m, 1H), 3.41 (dd, 1H), 4.79 (t, 1H), 5.29 (d, 1H), 7.35 (d, 1H), 7.57 (t, 1H), 7.63 (d, 1H), 7.67-7.79 (m, 3H).
By chromatography on a chiral phase [Method 12], the title compound was separated into its enantiomers: see Examples 30A and 31A.
Example 30A
tert-Butyl{2-[(1-hydroxy-2-methylpropan-2-yl)-amino]-2-oxo-1-[3-(trifluoromethyl)-phenyl]ethyl}-carbamate (enantiomer 1)




First-eluting enantiomer from the chromatographic enantiomer separation of the compound of Example 29A according to Method 12.
Chiral analytical HPLC [Method 13]: Rt=5.61 min
Example 31A
tert-Butyl{2-[(1-hydroxy-2-methylpropan-2-yl)-amino]-2-oxo-1-[3-(trifluoromethyl)-phenyl]ethyl}-carbamate (enantiomer 2)




Last-eluting enantiomer from the chromatographic enantiomer separation of the compound of Example 29A according to Method 12.
Chiral analytical HPLC [Method 13]: Rt=4.85 min
Example 32A
tert-Butyl{1-(2-chlorophenyl)-2-[(2-methoxyethyl)-amino]-2-oxoethyl}carbamate




A mixture of 250 mg (0.88 mmol) of [(tert-butoxycarbonyl)amino](2-chlorophenyl)acetic acid, 177 mg (1.31 mmol) of HOBt, 252 mg (1.31 mmol) of EDC and 72 mg (0.96 mmol) of 2-methoxyethanamine in 6.3 ml of DMF was stirred at RT for 2 h. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 269 mg (90% of theory) of the title compound.
LC-MS [Method 5]: Rt=0.88 min; MS [ESIpos]: m/z=343 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.38 (s, 9H), 3.18-3.29 (m, 2H), 3.22 (s, 3H), 3.29-3.37 (m, 2H), 5.45 (d, 1H), 7.28-7.34 (m, 2H), 7.35-7.46 (m, 2H), 7.49 (d, 1H), 8.06 (br. t, 1H).
Example 33A
tert-Butyl{2-[(2-hydroxyethyl)amino]-2-oxo-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate




Analogously to Example 18A, but without N,N′-diisopropylethylamine, 500 mg (1.57 mmol) of [(tert-butoxycarbonyl)amino][2-(trifluoromethyl)phenyl]acetic acid and 287 mg (4.70 mmol) of 2-ethanolamine gave 540 mg (95% of theory) of the title compound.
LC-MS [Method 4]: Rt=2.04 min; MS [ESIpos]: m/z=363 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.37 (br. s., 9H), 3.08-3.22 (m, 2H), 3.35-3.46 (m, 2H), 4.65 (t, 1H), 5.43 (d, 1H), 7.50 (t, 1H), 7.58 (d, 1H), 7.62-7.73 (m, 3H), 7.81-7.91 (m, 1H).
Example 34A
tert-Butyl{2-[(2-methoxyethyl)amino]-2-oxo-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate




Analogously to Example 18A, but withour N,N′-diisopropylethylamine, 500 mg (1.57 mmol) of [(tert-butoxycarbonyl)amino][2-(trifluoromethyl)phenyl]acetic acid and 176 mg (2.35 mmol) of 2-methoxyethanamine gave 510 mg (87% of theory) of the title compound.
LC-MS [Method 4]: Rt=2.28 min; MS [ESIpos]: m/z=377 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.37 (br. s., 9H), 3.19-3.29 (m, 2H), 3.23 (s, 3H), 3.28-3.41 (m, 2H), 5.43 (d, 1H), 7.46-7.55 (m, 1H), 7.56-7.61 (m, 1H), 7.62-7.75 (m, 3H), 7.91-8.01 (m, 1H).
Example 35A
tert-Butyl{2-[(2-hydroxyethyl)amino]-2-oxo-1-[3-(trifluoromethyl)phenyl]ethyl}carbamate




Analogously to Example 18A, but without N,N′-diisopropylethylamine, 319 mg (1.0 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 183 mg (3.0 mmol) of 2-ethanolamine gave 210 mg (58% of theory) of the title compound.
LC-MS [Method 4]: Rt=1.05 min; MS [ESIpos]: m/z=363 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.37 (d, 9H), 3.01-3.22 (m, 2H), 3.34-3.43 (m, 2H), 4.68 (t, 1H), 5.29 (d, 1H), 7.49 (d, 1H), 7.57 (t, 1H), 7.64 (d, 1H), 7.71 (d, 1H), 7.78 (s, 1H), 8.29 (t, 1H).
Example 36A
[(tert-Butoxycarbonyl)amino][3-(trifluoromethoxy)phenyl]acetic acid




Analogously to Example 26A, 2.0 g (8.5 mmol) of 3-(trifluoromethoxy)-DL-phenylalanine were reacted with 1.89 g (8.68 mmol) of di-tert-butyl dicarbonate. This gave 3.0 g (quant.) of the title compound.
LC-MS [Method 4]: Rt=1.05 min; MS [ESIpos]: m/z=236 (M+H−BOC)+; [ESIneg]: m/z=334 (M−H)−.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.39 (s, 9H), 5.22 (d, 1H), 7.31 (d, 1H), 7.38-7.55 (m, 3H), 7.75 (d, 1H), 12.96 (br. s., 1H).
Example 37A
tert-Butyl{2-[(2-hydroxyethyl)amino]-2-oxo-1-[3-(trifluoromethoxy)phenyl]ethyl}carbamate




Analogously to Example 18A, but without N,N′-diisopropylethylamine, 250 mg (0.75 mmol) of [(tert-butoxycarbonyl)amino][2-(trifluoromethoxy)phenyl]acetic acid and 55 mg (0.90 mmol) of 2-ethanolamine gave 258 mg (91% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.10 min; MS [ESIpos]: m/z=279 (M+H−BOC)+; [ESIneg]: m/z=377 (M−H)−.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.37 (s, 9H), 3.02-3.22 (m, 2H), 3.33-3.43 (m, 2H), 4.68 (t, 1H), 5.24 (d, 1H), 7.27 (d, 1H), 7.37-7.50 (m, 4H), 8.27 (t, 1H).
Example 38A
tert-Butyl{(1S)-3-[(2-hydroxyethyl)amino]-3-oxo-1-[2-(trifluoromethyl)phenyl]propyl}carbamate




Analogously to Example 32A, but with a reaction time of 15 h, 150 mg (0.45 mmol) of (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-(trifluoromethyl)phenyl]propanoic acid and 33 mg (0.54 mmol) of 2-aminoethanol gave 146 mg (86% of theory) of the title compound.
LC-MS [Method 1]: Rt=1.53 min; MS [ESIpos]: m/z=377 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.32 (s, 9H), 2.24-2.34 (m, 2H), 3.02-3.19 (m, 2H), 3.34-3.41 (m, 2H), 4.64 (t, 1H), 5.20-5.30 (m, 1H), 7.39-7.55 (m, 2H), 7.61-7.73 (m, 5H).
Example 39A
tert-Butyl{(1S)-3-[(2-hydroxyethyl)amino]-3-oxo-1-[3-(trifluoromethyl)phenyl]propyl}carbamate




Analogously to Example 18A, but without N,N′-diisopropylethylamine, 166 mg (0.50 mmol) of (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoic acid and 76 mg (1.24 mmol) of 2-aminoethanol gave 179 mg (94% of theory) of the title compound.
LC-MS [Method 4]: Rt=2.00 min; MS [ESIpos]: m/z=377 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 9H), 3.03 (q, 2H), 3.21-3.31 (m, 2H), 4.58 (t, 1H), 4.98 (q, 1H), 7.50-7.64 (m, 5H), 7.84 (t, 1H).
Example 40A
tert-Butyl{(1S)-3-[(2-methoxyethyl)amino]-3-oxo-1-[2-(trifluoromethyl)phenyl]propyl}carbamate




Analogously to Example 32A, but with a reaction time of 15 h, 142 mg (0.43 mmol) of (3S)-3-[(tert-butoxycarbonyl)amino]-3-[2-(trifluoromethyl)phenyl]propanoic acid and 38 mg (0.51 mmol) of 2-methoxyethanamine gave 133 mg (80% of theory) of the title compound.
LC-MS [Method 1]: Rt=1.76 min; MS [ESIpos]: m/z=391 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.32 (s, 9H), 2.23-2.35 (m, 2H), 3.13-3.25 (m, 2H), 3.23 (s, 3H), 3.30 (t, 2H), 5.19-5.30 (m, 1H), 7.40-7.52 (m, 2H), 7.62-7.70 (m, 3H), 7.76 (br. t, 1H).
Example 41A
tert-Butyl{(1S)-3-[(2-methoxyethyl)amino]-3-oxo-1-[3-(trifluoromethyl)phenyl]propyl}carbamate




Analogously to Example 18A, but without N,N′-diisopropylethylamine, 150 mg (0.45 mmol) of (3S)-3-[(tert-butoxycarbonyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoic acid and 41 mg (0.54 mmol) of 2-methoxyethanamine gave 167 mg (95% of theory) of the title compound.
LC-MS [Method 4]: Rt=2.20 min; MS [ESIpos]: m/z=391 (M+H)30 
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 9H), about 2.52 (m, 2H, partially under the DMSO signal), 3.04-3.26 (m, 4H), 3.16 (s, 3H), 4.97 (br. q, 1H), 7.46-7.66 (m, 5H), 7.93 (t, 1H).
Example 42A
tert-Butyl(2-oxo-2-{[2-(trifluoromethoxy)ethyl]amino}-1-[3-(trifluoromethyl)phenyl]ethyl)-carbamate (racemate)




Analogously to Example 18A, 250 mg (0.78 mmol) of [(tert-butoxycarbonyl)amino][3-(trifluoromethyl)phenyl]acetic acid and 156 mg (0.94 mmol) of 2-(trifluoromethoxy)ethanamine hydrochloride gave 320 mg (95% of theory) of the title compound.
LC-MS [Method 4]: Rt=2.52 min; MS [ESIpos]: m/z=431 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.38 (s, 9H), 3.27-3.48 (m, 2H), 3.94-4.07 (m, 2H), 5.29 (d, 1H), 7.53-7.60 (m, 2H), 7.62-7.67 (m, 1H), 7.70 (d, 1H), 7.78 (s, 1H), 8.53 (t, 1H).
By chromatography on a chiral phase [Method 14a], the title compound was separated into its two enantiomers: see Examples 43A and 44A.
Example 43A
tert-Butyl(2-oxo-2-{[2-(trifluoromethoxy)ethyl]amino}-1-[3-(trifluoromethyl)phenyl]ethyl)-carbamate (enantiomer 1)




First-eluting enantiomer (150 mg) from the chromatographic enantiomer separation of the compound of Example 42A according to Method 14a.
Chiral analytical HPLC [Method 15a]: Rt=3.56 min
Example 44A
tert-Butyl(2-oxo-2-{[2-(trifluoromethoxy)ethyl]amino}-1-[3-(trifluoromethyl)phenyl]ethyl)-carbamate (enantiomer 2)




Last-eluting enantiomer (128 mg) from the chromatographic enantiomer separation of the compound of Example 42A according to Method 14a.
Chiral analytical HPLC [Method 15a]: Rt=3.89 min
Example 45A
Ethyl 1-({amino[3-(trifluoromethyl)phenyl}acetyl]amino)cyclopropanecarboxylate hydrochloride




262 mg (0.61 mmol) of the compound of Example 17A were dissolved in 4 ml of dichloromethane, and 4 ml of a 4N solution of hydrogen chloride in dioxane were added. The solution was stirred at RT for 3 h and then freed from the volatile components on a rotary evaporator. The residue was dried under high vacuum. This gave 223 mg (quant.) of the title compound.
LC-MS [Method 3]: Rt=0.79 min; MS [ESIpos]: m/z=331 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.95 (t, 3H), 0.97-1.08 (m, 2H), 1.27-1.34 (m, 1H), 1.46-1.53 (m, 1H), 3.85-3.99 (m, 2H), 5.08 (s, 1H), 7.73 (t, 1H), 7.81-7.87 (m, 2H), 7.95 (s, 1H), 8.73 (br. s., 3H), 9.24 (s, 1H).
Examples 46A to 61A in Table 1 were prepared by the same method. The reaction times to complete conversion were between 0.5 h and 16 h. The yields are greater than 90% of theory.










TABLE 1





Exam- 

Starting 
Name of the example and 


ple No.
Structure
material
analytical data







46A




18A
methyl N-{amino[3-(trifluoromethyl)- phenyl]acetyl}-2-methylalaninate hydrochloride LC-MS [Method 2]: Rt = 1.32 min; MS [ESIpos]: m/z = 319 (M + H)+


 


47A




19A
methyl N-{amino[3-(trifluoromethyl)- phenyl]acetyl}-beta-alaninate hydrochloride LC-MS [Method 3]: Rt = 0.66 min; MS [ESIpos]: m/z = 305 (M + H)+


 


48A




21A
N3-{amino[3-(trifluoromethyl)- phenyl]acetyl}-beta-alaninamide hydrochloride (enantiomer 1) LC-MS [Method 3]: Rt = 0.28 min; MS [ESIpos]: m/z = 290 (M + H)+


 


49A




22A
N3-{amino[3-(trifluoromethyl)- phenyl]acetyl}-beta-alaninamide hydrochloride (enantiomer 2) LC-MS [Method 2]: Rt = 0.86 min; MS [ESIpos]: m/z = 290 (M + H)+


 


50A




30A
2-amino-N-(1-hydroxy-2- methylpropan-2-yl)-2-[3- (trifluoromethyl)phenyl]acetamide hydrochloride (enantiomer 1) LC-MS [Method 2]: Rt = 1.22 min; MS [ESIpos]: m/z = 291 (M + H)+


 


51A




31A
2-amino-N-(1-hydroxy-2- methylpropan-2-yl)-2-[3- (trifluoromethyl)phenyl]acetamide hydrochloride (enantiomer 2) LC-MS [Method 2]: Rt = 1.22 min; MS [ESIpos]: m/z = 291 (M + H)+


 


52A




33A
2-amino-N-(2-hydroxyethyl)-2-[2- (trifluoromethyl)phenyl]acetamide hydrochloride (purity 75%) LC-MS [Method 2]: Rt = 0.22 min; MS [ESIpos]: m/z = 263 (M + H)+


 


53A




34A
2-amino-N-(2-methoxyethyl)-2-[2- (trifluoromethyl)phenyl]acetamide hydrochloride LC-MS [Method 2]: Rt = 0.93 min; MS [ESIpos]: m/z = 277 (M + H)+


 


54A




35A
2-amino-N-(2-hydroxyethyl)-2-[3- (trifluoromethyl)phenyl]acetamide hydrochloride LC-MS [Method 2]: Rt = 0.97 min; MS [ESIpos]: m/z = 263 (M + H)+


 


55A




37A
2-amino-N-(2-hydroxyethyl)-2-[3- (trifluoromethoxy)phenyl]acetamide hydrochloride LC-MS [Method 2]: Rt = 1.01 min; MS [ESIpos]: m/z = 279 (M + H)+


 


56A




38A
(3S)-3-amino-N-(2-hydroxyethyl)-3- [2-(trifluoromethyl)phenyl]- propanamide hydrochloride LC-MS [Method 3]: Rt = 0.30 min; MS [ESIpos]: m/z = 277 (M + H)+


 


57A




39A
(3S)-3-amino-N-(2-hydroxyethyl)-3- [3-(trifluoromethyl)phenyl]- propanamide hydrochloride LC-MS [Method 2]: Rt = 0.90 min; MS [ESIpos]: m/z = 277 (M + H)+


 


58A




40A
(3S)-3-amino-N-(2-methoxyethyl)-3- [2-(trifluoromethyl)phenyl]- propanamide hydrochloride LC-MS [Method 3]: Rt = 0.52 min; MS [ESIpos]: m/z = 291 (M + H)+


 


59A




41A
(3S)-3-amino-N-(2-methoxyethyl)-3- [3-(trifluoromethyl)phenyl]- propanamide hydrochloride LC-MS [Method 3]: Rt = 0.62 min; MS [ESIpos]: m/z = 291 (M + H)+


 


60A




43A
2-amino-N-[2-(trifluoromethoxy)- ethyl]-2-[3-(trifluoromethyl)phenyl]- acetamide hydrochloride  (enantiomer 1) LC-MS [Method 3]: Rt = 0.81 min; MS [ESIpos]: m/z = 331 (M + H)+


 


61A




44A
2-amino-N-[2-(trifluoromethoxy)- ethyl]-2-[3-(trifluoromethyl)phenyl]- acetamide hydrochloride  (enantiomer 2) LC-MS [Method 3]: Rt = 0.81 min; MS [ESIpos]: m/z = 331 (M + H)+









Example 62A
N2-{Amino[2-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide hydrochloride




4.45 ml of a 4N solution of hydrogen chloride in dioxane were added to 922 mg (0.48 mmol) of the compound of Example 24A. The solution was stirred at RT for 1 h and then freed from the volatile components on a rotary evaporator. The residue was stirred with 10 ml of diethyl ether. The solid was isolated by filtration and dried under high vacuum. This gave 167 mg (96% of theory) of the title compound.
LC-MS [Method 5]: Rt=0.36 min; MS [ESIpos]: m/z=304 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.34 (s, 3H), 1.40 (s, 3H), 5.14 (s, 1H), 7.13 (s, 1H), 7.37 (s, 1H), 7.68 (t, 1H), 7.75-7.89 (m, 3H), 8.21 (br. s., 1H), 8.94 (br. s., 3H).
Examples 63A to 66A in Table 2 were prepared analogously to Example 62A. The yields are in each case greater than 90% of theory.










TABLE 2





Exam-

Starting
Name of the example and 


ple No.
Structure
material
analytical data







63A




23A
N2-{amino[3-(trifluoromethyl)- phenyl]acetyl}-2- methylalaninamide hydrochloride LC-MS [Method 2]: Rt = 1.05 min; MS [ESIpos]: m/z = 304 (M + H)+


 


64A




25A
N2-[amino(2-chlorophenyl)acetyl]- 2-methylalaninamide  hydrochloride LC-MS [Method 5]: Rt = 0.26 min; MS [ESIpos]: m/z = 270 (M + H)+


 


65A




27A
N2-[amino(2,3-dichlorophenyl)- acetyl]-2-methylalaninamide  hydrochloride LC-MS [Method 5]: Rt = 0.44 min; MS [ESIpos]: m/z = 304 (M + H)+


 


66A




32A
2-amino-2-(2-chlorophenyl)-N- (2-methoxyethyl)acetamide hydrochloride LC-MS [Method 5]: Rt = 0.29 min; MS [ESIpos]: m/z = 243 (M + H)+









Example 67A
Methyl N-{(3S)-3-amino-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate




130 mg (0.30 mmol) of the compound of Example 28A were dissolved in 2 ml of acetonitrile, and 2 ml of a 4N solution of hydrogen chloride in dioxane were added. The solution was stirred at RT for 3 h and then freed from the volatile components on a rotary evaporator. The residue was dried under high vacuum. This gave 108 mg (97% of theory) of the title compound.
LC-MS [Method 3]: Rt=0.75 min; MS [ESIpos]: m/z=333 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.16 (s, 3H), 1.24 (s, 3H), 2.78-2.91 (m, 2H), 3.41 (s, 3H), 4.66-4.76 (m, 1H), 7.63-7.70 (m, 1H), 7.73-7.81 (m, 2H), 7.87 (s, 1H), 8.48-8.68 (m, 4H).
Working Examples
Example 1
Ethyl 1-({[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylate (diastereomer mixture)




A mixture of 50 mg (0.14 mmol) of the compound of Example 8A, 55 mg (0.15 mmol) of the compound of Example 45A, 39 mg (0.21 mmol) of EDC, 28 mg (0.21 mmol) of HOBt and 29 μl (0.16 mmol) of N,N′-diisopropylethylamine in 1.4 ml of DMF was stirred at RT for 3 h and then separated by preparative HPLC [Method 6]. The suitable fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 82 mg (88% of theory) of the title compound as a diastereomer mixture.
LC-MS [Method 3]: Rt=1.31 min; MS [ESIpos]: m/z=678 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.91 (td interpreted as 1 t each per diastereomer, 3H), 0.95-1.08 (m, 2H), 1.25-1.33 (m, 1H), 1.38-1.46 (m, 1H), 3.78-4.01 (m, 4H), 4.18-4.33 (m, 1H), 4.52-4.65 (m, 2H), 5.54 (d, 1H), 6.89 (dd interpreted as 1 d each per diastereomer, 1H), 7.58-7.65 (m, 3H), 7.66-7.71 (m, 1H), 7.71-7.77 (m, 3H), 7.82 (s, 1H), 9.07 (d, 1H), 9.09 (s, 1H).
Example 2
1-({[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylic acid (diastereomer mixture)




78 mg (0.115 mmol) of the compound of Example 1 were dissolved in 2.2 ml of methanol, and 460 μl of a 1M aqueous lithium hydroxide solution (0.46 mmol) were added. The mixture was stirred at RT overnight and then adjusted to pH 2 by addition of 1N hydrochloric acid, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 64 mg (86% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.19 min; MS [ESIpos]: m/z=650 (M+H)+
By preparative HPLC on a chiral phase [Method 14a], the two diastereomers were separated: see Example 3 and Example 4.
Example 3
1-({[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylic acid (diastereomer 1)




First-eluting diastereomer from the diastereomer separation of 64 mg of the compound of Example 2 according to Method 14a. After chromatography on the chiral phase, the product obtained was purified from solvent contaminants by preparative HPLC [Method 6]. This gave 14 mg of the title compound.
Chiral analytical HPLC [Method 15a]: Rt=4.60 min
LC-MS [Method 1]: Rt=1.92 min; MS [ESIpos]: m/z=650 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.84-0.93 (m, 1H), 0.93-1.02 (m, 1H), 1.25-1.42 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.34 (m, 1H), 4.52-4.65 (m [AB], 2H), 5.55 (d, 1H), 6.91 (br. d, 1H), 7.55-7.78 (m, 6H), 7.82 (s, 1H), 8.99-9.07 (m, 2H), 12.43 (s, 1H).
Example 4
1-({[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylic acid (diastereomer 2)




Last-eluting diastereomer from the diastereomer separation of 64 mg of the compound of Example 2 according to Method 14a. After chromatography on the chiral phase, the product obtained was purified from solvent contaminants by preparative HPLC [Method 6]. This gave 16 mg of the title compound.
Chiral analytical HPLC [Method 15a]: Rt=5.85 min
LC-MS [Method 1]: Rt=1.91 min; MS [ESIpos]: m/z=650 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.83-0.92 (m, 1H), 0.93-1.02 (m, 1H), 1.25-1.42 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.34 (m, 1H), 4.52-4.67 (m [AB], 2H), 5.55 (d, 1H), 6.89 (d, 1H), 7.55-7.78 (m, 7H), 7.83 (s, 1H), 8.89-9.14 (m, 2H), 12.43 (s, 1H).
Example 5
Ethyl 1-({({[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino) [3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylate (racemate)




Analogously to Example 1, 50 mg (0.17 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 88A) and 69 mg (0.19 mmol) of the compound of Example 45A were used to prepare the title compound. This gave 83 mg (80% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.27 min; MS [ESIpos]: m/z=606 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.51-0.60 (m, 2H), 0.85-0.92 (m, 2H), 0.91 (t, 3H), 0.94-1.08 (m, 2H), 1.24-1.33 (m, 1H), 1.38-1.46 (m, 1H), 3.17 (tt, 1H), 3.82-3.98 (m, 2H), 4.45-4.59 (m [AB], 2H), 5.52 (d, 1H), 7.54-7.65 (m, 3H), 7.65-7.71 (m, 1H), 7.71-7.84 (m, 4H), 9.03 (d, 1H), 9.08 (s, 1H).
Example 6
1-({({[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino)[3-(trifluoromethyl)phenyl}acetyl]amino)cyclopropanecarboxylic acid (racemate)




64 mg (0.106 mmol) of the compound of Example 5 were dissolved in 3 ml of methanol, and 422 μl of a 1M aqueous lithium hydroxide solution (0.42 mmol) were added. The mixture was stirred at RT overnight. Since the reaction was very slow, another 210 μl (0.21 mmol) of a 1M sodium hydroxide solution were added and the mixture was stirred at RT for another 5 days. By addition of 1N hydrochloric acid, the mixture was adjusted to pH 2, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 37 mg (61% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.15 min; MS [ESIpos]: m/z=578 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.51-0.61 (m, 2H), 0.83-0.93 (m, 3H), 0.94-1.02 (m, 1H), 1.25-1.41 (m, 2H), 3.17 (tt, 1H), 4.47-4.58 (m [AB], 2H), 5.54 (d, 1H), 7.55-7.62 (m, 3H), 7.64-7.68 (m, 1H), 7.70 (d, 1H), 7.76-7.84 (m, 3H), 8.98 (d, 1H), 9.01 (s, 1H), 12.43 (br. s., 1H).
Example 7
Ethyl 1-({({[3-(5-chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino) [3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylate (racemate)




Analogously to Example 1, 25 mg (79 μmol) of the compound of Example 15A and 32 mg (87 μmol) of the compound of Example 45A were employed. Purification by HPLC [Method 7] gave 47 mg (95% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.05 min; MS [ESIpos]: m/z=630 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.91 (t, 3H), 0.95-1.09 (m, 2H), 1.24-1.32 (m, 1H), 1.38-1.46 (m, 1H), 3.19 (s, 3H), 3.53 (t, 2H), 3.84-3.94 (m, 2H), 3.96 (t, 2H), 4.49-4.60 (m [AB], 2H), 5.53 (d, 1H), 7.26 (d, 1H), 7.55 (d, 1H), 7.62 (t, 1H), 7.69 (d, 1H), 7.74 (d, 1H), 7.81 (s, 1H), 9.07 (d, 1H), 9.09 (s, 1H).
Example 8
1-({({[3-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino)[3-(trifluoromethyl)phenyl]acetyl}amino)cyclopropanecarboxylic acid (racemate)




43 mg (68 μmol) of the compound of Example 7 were dissolved in 3 ml of methanol, and 273 μl of a 1M aqueous lithium hydroxide solution (0.27 mmol) were added. The mixture was stirred at RT overnight and then acidified by addition of 1N hydrochloric acid and diluted with water. The precipitated solid was filtered off with suction, washed with a little water and dried in a vacuum drying cabinet at 50° C. This gave 32 mg (74% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.16 min; MS [ESIpos]: m/z=602 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.84-0.93 (m, 1H), 0.94-1.04 (m, 1H), 1.25-1.43 (m, 2H), 3.19 (s, 3H), 3.50-3.60 (m, 2H), 3.97 (t, 2H), 4.46-4.64 (m, 2H), 5.54 (d, 1H), 7.26 (d, 1H), 7.53-7.63 (m, 2H), 7.69 (dd, 2H), 7.82 (s, 1H), 8.98-9.08 (m, 2H), 12.44 (br. s., 1H).
Example 9
Methyl N-{({[3-(5-chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)[3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninate (racemate)




Analogously to Example 1, 25 mg (79 μmol) of the compound of Example 15A and 31 mg (87 μmol) of the compound of Example 46A were employed. Purification by HPLC [Method 7] gave 44 mg (90% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.05 min; MS [ESIpos]: m/z=618 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (s, 3H), 1.40 (s, 3H), 3.20 (s, 3H), 3.44 (s, 3H), 3.54 (t, 2H), 3.97 (t, 2H), 4.49-4.61 (m, 2H), 5.63 (d, 1H), 7.26 (d, 1H), 7.56 (d, 1H), 7.59-7.65 (m, 1H), 7.66-7.72 (m, 2H), 7.76 (s, 1H), 8.84 (s, 1H), 9.02 (d, 1H).
Example 10
N-{({[3-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino) [3-(trifluoromethyl)phenyl}acetyl]-2-methylalanine (racemate)




Analogously to Example 8, 40 mg (65 μmol) of the compound of Example 9 were hydrolysed. This gave 31 mg (75% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.20 min; MS [ESIpos]: m/z=604 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (s, 3H), 1.38 (s, 3H), 3.20 (s, 3H), 3.54 (t, 2H), 3.97 (t, 2H), 4.49-4.61 (m, 2H), 5.65 (d, 1H), 7.26 (d, 1H), 7.54-7.62 (m, 2H), 7.63-7.73 (m, 2H), 7.79 (s, 1H), 8.68 (s, 1H), 9.00 (d, 1H), 12.28 (br. s., 1H).
Example 11
Methyl N-{({[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino)[3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninate (racemate)




Analogously to Example 1, 50 mg (0.17 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 88A) and 72 mg (0.19 mmol) of the compound of Example 46A were used to prepare the title compound. This gave 89 mg (88% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.28 min; MS [ESIpos]: m/z=594 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.40-0.68 (m, 2H), 0.79-1.00 (m, 2H), 1.27 (s, 3H), 1.40 (s, 3H), 3.18 (dt, 1H), 3.44 (s, 3H), 4.46-4.58 (m [AB], 2H), 5.62 (d, 1H), 7.55-7.64 (m, 3H), 7.65-7.72 (m, 2H), 7.74-7.83 (m, 3H), 8.83 (s, 1H), 8.98 (d, 1H).
Example 12
N-{({[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino) [3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (racemate)




Analogously to Example 6, 68 mg (114 μmol) of the compound of Example 9 were hydrolysed. This gave 55 mg (83% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.19 min; MS [ESIpos]: m/z=580 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.51-0.62 (m, 2H), 0.84-0.94 (m, 2H), 1.27 (s, 3H), 1.38 (s, 3H), 3.18 (tt, 1H), 4.52 (s, 2H), 5.64 (d, 1H), 7.54-7.61 (m, 3H), 7.63-7.68 (m, 1H), 7.70 (d, 1H), 7.76-7.84 (m, 3H), 8.67 (s, 1H), 8.96 (d, 1H), 12.27 (s, 1H).
Example 13
Methyl N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alaninate (diastereomer mixture)




Analogously to Example 1, 50 mg (0.14 mmol) of the compound of Example 8A and 51 mg (0.15 mmol) of the compound of Example 47A were used to prepare the title compound. This gave 88 mg (99% of theory) of the title compound as a diastereomer mixture.
LC-MS [Method 3]: Rt=1.25 min; MS [ESIpos]: m/z=652 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.44 (t, 2H), 3.25-3.31 (m, 2H), 3.52 (s, 3H), 3.82 (dd, 1H), 3.91-4.00 (m, 1H), 4.19-4.33 (m, 1H), 4.52-4.66 (m, 2H), 5.55 (d, 1H), 6.89 (t interpreted as 1 d each per diastereomer, 1H), 7.55-7.80 (m, 8H), 8.60 (t interpreted as 1 d each per diastereomer, 1H), 9.05 (d, 1H).
Example 14
N-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alanine (diastereomer mixture)




78 mg (0.12 mmol) of the compound of Example 13 were dissolved in 2.3 ml of methanol, and 360 μl of a 1M aqueous lithium hydroxide solution (0.36 mmol) were added. The mixture was stirred at RT for 1 h and then adjusted to pH 2 by addition of 1N hydrochloric acid, diluted with a little DMSO and separated by preparative HPLC [Method 6]. This gave 67 mg (88% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.17 min; MS [ESIpos]: m/z=638 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.36 (t, 2H), 3.17-3.30 (m, 2H), 3.82 (dd, 1H), 3.96 (br. d, 1H), 4.17-4.35 (m, 1H), 4.50-4.68 (m, 2H), 5.57 (d, 1H), 6.89 (t interpreted as 1 d each per diastereomer, 1H), 7.52-7.82 (m, 8H), 8.59 (t interpreted as 1 d each per diastereomer, 1H), 9.04 (d, 1H), 12.23 (br. s., 1H).
Example 15
Methyl N-{({[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino) [3-(trifluoromethyl)phenyl]acetyl}-beta-alaninate (racemate)




A mixture of 50 mg (0.14 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 88A), 49 mg (0.26 mmol) of EDC and 35 mg (0.26 mmol) of HOBt in 1.7 ml of DMF was stirred at RT for 20 min 64 mg (0.19 mmol) of the compound of Example 47A and 36 μl (0.20 mmol) of N,N′-diisopropylethylamine were added, and the mixture was stirred further overnight at RT and then separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 80 mg (81% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.21 min; MS [ESIpos]: m/z=580 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.50-0.60 (m, 2H), 0.84-0.94 (m, 2H), 2.41-2.47 (m, 2H), 3.17 (tt, 1H), 3.25-3.31 (m, 2H), 3.52 (s, 3H), 4.44-4.59 (m [AB], 2H), 5.55 (s, 1H), 7.53-7.63 (m, 3H), 7.63-7.72 (m, 2H), 7.72-7.83 (m, 3H), 8.59 (t, 1H), 9.01 (d, 1H).
Example 16
N-{({[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino) [3-(trifluoromethyl)phenyl]acetyl}-beta-alanine (racemate)




Analogously to Example 2, 52 mg (90 μmol) of the compound of Example 15 were hydrolysed and purified. This gave 33 mg (65% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.13 min; MS [ESIpos]: m/z=566 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.52-0.61 (m, 2H), 0.82-0.95 (m, 2H), 2.36 (t, 2H), 3.12-3.30 (m, 3H), 4.46-4.59 (m, 2H), 5.56 (d, 1H), 7.52-7.62 (m, 3H), 7.69 (t, 2H), 7.74-7.82 (m, 3H), 8.58 (t, 1H), 9.01 (d, 1H), 12.25 (br. s., 1H).
Example 17
N3-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alaninamide (diastereomer 1)




A mixture of 19 mg (51 μmol) of the compound of Example 8A, 20 mg (61 μmol) of the compound of Example 48A, 15 mg (77 μmol) of EDC, 10 mg (77 μmol) of HOBt and 13 μl (77 μmol) of N,N′-diisopropylethylamine in 1 ml of DMF was stirred at RT for 20 min, 1 ml of 1N hydrochloric acid was then added and the mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 30 mg (92% of theory) of the title compound.
LC-MS [Method 1]: Rt=1.79 min; MS [ESIpos]: m/z=637 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.15-2.25 (m, 2H), 3.16-3.30 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.18-4.34 (m, 1H), 4.59 (s, 2H), 5.58 (d, 1H), 6.82 (br. s., 1H), 6.90 (d, 1H), 7.29 (br. s., 1H), 7.55-7.68 (m, 4H), 7.69-7.77 (m, 3H), 7.78 (s, 1H), 8.55 (t, 1H), 9.04 (d, 1H).
Example 18
N3-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-beta-alaninamide (diastereomer 2)




Analogously to Example 17, 19 mg (51 μmol) of the compound of Example 8A and 25 mg (61 μmol) of the compound of Example 49A gave the title compound. Yield: 19 mg (58% of theory).
LC-MS [Method 1]: Rt=1.77 min; MS [ESIpos]: m/z=637 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.13-2.26 (m, 2H), 3.16-3.32 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.19-4.33 (m, 1H), 4.53-4.65 (m [AB], 2H), 5.57 (d, 1H), 6.82 (br. s., 1H), 6.89 (d, 1H), 7.29 (br. s., 1H), 7.62 (d, 4H), 7.73 (s, 3H), 7.77-7.81 (m, 1H), 8.55 (t, 1H), 9.04 (d, 1H).
Example 19
N3-{(2R)-2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-beta-alaninamide




Analogously to Example 17, 40 mg (69 μmol) of the compound of Example 16A and 25 mg (103 μmol) of beta-alaninamide hydrochloride gave the title compound. Yield: 38 mg (85% of theory).
LC-MS [Method 1]: Rt=1.83 min; MS [ESIpos]: m/z=651 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.84 (s, 3H), 2.09-2.22 (m, 2H), 3.13-3.28 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.19-4.36 (m, 1H), 4.58 (s, 2H), 6.76 (br. s., 1H), 6.90 (d, 1H), 7.25 (br. s., 1H), 7.51-7.58 (m, 1H), 7.60-7.66 (m, 3H), 7.69 (d, 1H), 7.75 (d, 3H), 7.90 (t, 1H), 8.69 (s, 1H).
Example 20
Methyl N-{(2R)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate




Analogously to Example 17, 40 mg (69 μmol) of the compound of Example 16A and 16 mg (103 μmol) of methyl 2-methylalaninate hydrochloride gave the title compound. Yield: 36 mg (77% of theory).
LC-MS [Method 1]: Rt=2.24 min; MS [ESIpos]: m/z=680 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.26 (s, 3H), 1.29 (s, 3H), 1.82 (s, 3H), 3.52 (s, 3H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.17-4.32 (m, 1H), 4.52-4.63 (m [AB], 2H), 6.89 (d, 1H), 7.56-7.67 (m, 4H), 7.68-7.79 (m, 4H), 7.98 (s, 1H), 8.69 (s, 1H).
Example 21
N-{(2R)-2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine




32 mg (47 μmol) of the compound of Example 20 were dissolved in 1.6 ml of acetonitrile, and 235 μl (235 μmol) of a 1M aqueous lithium hydroxide solution were added. The mixture was stirred at RT overnight, 1 ml of 1N hydrochloric acid was then added and the mixture was separated by preparative HPLC [Method 6]. This gave 31 mg (99% of theory) of the title compound.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (s, 3H), 1.29 (s, 3H), 1.80 (s, 3H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.19-4.33 (m, 1H), 4.51-4.64 (m [AB], 2H), 6.90 (d, 1H), 7.52-7.58 (m, 1H), 7.59-7.66 (m, 3H), 7.69-7.78 (m, 4H), 7.82 (s, 1H), 8.71 (s, 1H), 12.29 (s, 1H).
Example 22
N2-{(2R)-2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl}propanoyl]-2-methylalaninamide




A mixture of 31 mg (47 μmol) of the compound of Example 21, 13 mg (70 μmol) of EDC and 9.4 mg (70 μmol) of HOBt in 2 ml of DMF was stirred at RT for 20 min and then poured into 2 ml of ammonia (35% strength solution in water). The reaction mixture was stirred at RT for 30 min, then briefly concentrated on a rotary evaporator, acidified with 1N hydrochloric acid and separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 29 mg (92% of theory) of the title compound.
LC-MS [Method 3]: Rt=1.21 min; MS [ESIpos]: m/z=665 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (s, 3H), 1.30 (s, 3H), 1.78 (s, 3H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.20-4.36 (m, 1H), 4.56-4.71 (m [AB], 2H), 6.85 (s, 2H), 6.89 (d, 1H), 7.55-7.69 (m, 4H), 7.73-7.84 (m, 5H), 8.91 (s, 1H).
Example 23
Methyl N-{[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninate (diastereomer mixture)




Analogously to Example 1, 398 mg (1.09 mmol) of the compound of Example 8A and 457 mg (1.20 mmol) of the compound of Example 46A were used to prepare the title compound. This gave 664 mg (91% of theory) of the title compound as a diastereomer mixture.
LC-MS [Method 3]: Rt=1.32 min; MS [ESIpos]: m/z=666 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (s, 3H), 1.40 (s, 3H), 3.44 (d, interpreted as 3.440 and 3.444, 1 s each per diastereomer, 3H in total), 3.83 (dd, 1H), 3.96 (br. dd, 1H), 4.20-4.33 (m, 1H), 4.52-4.65 (m, 2H), 5.64 (d, 1H), 6.86-6.92 (dd, interpreted as 6.89 and 6.90, 1 d each per diastereomer, 1H), 7.58-7.80 (m, 7H), 8.84 (s, 1H), 9.02 (d, 1H).
Example 24
N-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (diastereomer mixture)




Analogously to Example 2, 69 mg (0.104 mmol) of the compound of Example 23 were hydrolysed and purified. This gave 63 mg (93% of theory) of the title compound as a diastereomer mixture.
LC-MS [Method 3]: Rt=1.22 min; MS [ESIpos]: m/z=652 (M+H)+
By preparative HPLC on a chiral phase [Method 14a], the two diastereomers were separated: see Example 25 and Example 26.
Example 25
N-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (diastereomer 1)




First-eluting diastereomer from the diastereomer separation of 63 mg of the compound of Example 24 according to Method 14a. After chromatography on the chiral phase, the product obtained was purified from solvent contaminants by preparative HPLC [Method 6]. This gave 15 mg of the title compound.
Chiral analytical HPLC [Method 15a]: Rt=5.02 min
LC-MS [Method 1]: Rt=1.99 min; MS [ESIpos]: m/z=652 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.28 (s, 3H), 1.38 (s, 3H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.19-4.34 (m, 1H), 4.59 (s, 2H), 5.66 (d, 1H), 6.91 (d, 1H), 7.55-7.77 (m, 7H), 7.79 (s, 1H), 8.62-8.73 (m, 1H), 9.00 (d, 1H), 12.28 (s, 1H).
Example 26
N-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalanine (diastereomer 2)




Last-eluting diastereomer from the diastereomer separation of 63 mg of the compound of Example 24 according to Method 14a. After chromatography on the chiral phase, the product obtained was purified from solvent contaminants by preparative HPLC [Method 6]. This gave 12 mg of the title compound.
Chiral analytical HPLC [Method 15a]: Rt=6.77 min
LC-MS [Method 1]: Rt=1.99 min; MS [ESIpos]: m/z=652 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (s, 3H), 1.38 (s, 3H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.18-4.34 (m, 1H), 4.53-4.65 (m [AB], 2H), 5.66 (d, 1H), 6.89 (d, 1H), 7.56-7.77 (m, 7H), 7.79 (s, 1H), 8.67 (s, 1H), 9.00 (d, 1H), 12.27 (s, 1H).
Example 27
N2-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (diastereomer mixture)




Analogously to Example 1, 195 mg (0.53 mmol) of the compound of Example 8A and 198 mg (0.58 mmol) of the compound of Example 63A gave the title compound as a diastereomer mixture: 330 mg (95% of theory).
LC-MS [Method 4]: Rt=2.22 min; MS [ESIpos]: m/z=651 (M+H)+
By preparative HPLC on a chiral phase [Method 14b], the two diastereomers were separated: see Example 28 and Example 29.
Example 28
N2-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (diastereomer 1)




First-eluting diastereomer from the diastereomer separation of 320 mg of the compound of Example 27 according to Method 14b. After chromatography on the chiral phase, the product obtained was purified from solvent contaminants by preparative HPLC [Method 6]. This gave 130 mg of the title compound.
Chiral analytical HPLC [Method 15b]: Rt=3.52 min
LC-MS [Method 1]: Rt=1.90 min; MS [ESIpos]: m/z=651 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.28 (s, 3H), 1.33 (s, 3H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.19-4.34 (m, 1H), 4.59 (s, 2H), 5.60 (d, 1H), 6.89 (br. s, 1H), 6.91 (d, 1H), 6.97 (br. s., 1H), 7.56-7.68 (m, 4H), 7.71-7.77 (m, 3H), 7.81 (s, 1H), 8.43 (s, 1H), 8.97 (d, 1H).
Example 29
N2-{[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][3-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (diastereomer 2)




Last-eluting diastereomer from the diastereomer separation of 320 mg of the compound of Example 27 according to Method 14b. After chromatography on the chiral phase, the product obtained was purified from solvent contaminants by preparative HPLC [Method 6]. This gave 141 mg of the title compound.
Chiral analytical HPLC [Method 15b]: Rt=5.01 min
LC-MS [Method 1]: Rt=1.89 min; MS [ESIpos]: m/z=651 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (s, 3H), 1.33 (s, 3H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.19-4.33 (m, 1H), 4.52-4.65 (m [AB], 2H), 5.61 (s, 1H), 6.89 (br. s, 2H), 6.97 (s, 1H), 7.55-7.77 (m, 7H), 7.81 (s, 1H), 8.44 (s, 1H), 8.96 (d, 1H).
Example 30
N2-{({[3-(4-Chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino) [2-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (racemate)




Analogously to Example 1, 25 mg (69 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 156A) and 28 mg (76 mol) of the compound of Example 62A were employed. Purification by HPLC [Method 7] gave 28 mg (63% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.01 min; MS [ESIpos]: m/z=647 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 3H), 1.37 (s, 3H), 4.51-4.68 (m [AB], 2H), 5.02 (s, 2H), 5.65 (d, 1H), 7.00-7.18 (m, 5H), 7.26-7.34 (m, 1H), 7.49-7.59 (m, 5H), 7.66-7.77 (m, 3H), 8.03 (s, 1H), 9.15 (d, 1H).
Example 31
N2-{[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino][2-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (racemate)




Analogously to Example 1, 25 mg (72 μmol) of the compound of Example 11A and 29 mg (79 μmol) of the compound of Example 62A were employed. Purification by HPLC [Method 7] gave 32 mg (70% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.04 min; MS [ESIpos]: m/z=633 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.36 (s, 3H), 1.38 (s, 3H), 4.52-4.68 (m [AB], 2H), 5.65 (d, 1H), 6.85 (dq, 1H), 7.03 (br. s, 1H), 7.06 (br. s, 1H), 7.17 (dq, 1H), 7.55 (t, 1H), 7.61-7.78 (m, 7H), 8.02 (s, 1H), 9.16 (d, 1H).
Example 32
N2-{({[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino) [2-(trifluoromethyl)phenyl]acetyl}-2-methylalaninamide (racemate)




A solution of 25 mg (39 μmol) of the compound of Example 31 in 10 ml of methanol was hydrogenated in an H-Cube fitted with a platinum cartridge (5% Pt/C) (continuous-flow hydrogenation apparatus from Thales Nano, Budapest, Model HC-2-SS) at a flow rate of 1 ml/min, at 60° C. and under hydrogen at standard pressure. The resulting solution was freed from methanol on a rotary evaporator, and the residue was dissolved in 2 ml of acetonitrile and purified by preparative HPLC [Method 7]. This gave 8 mg (32% of theory) of the title compound.
LC/MS [Method 5]: Rt=0.96 min; m/z=635 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 3H), 1.38 (s, 3H), 2.56-2.66 (m, 2H), 3.98 (t, 2H), 4.46-4.62 (m [AB], 2H), 5.63 (d, 1H), 7.03 (br.s, 1H), 7.04 (br.s, 1H), 7.51-7.58 (m, 1H), 7.60-7.77 (m, 7H), 8.01 (s, 1H), 9.11 (d, 1H).
Example 33
N2-[(2-Chlorophenyl)({[3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)acetyl]-2-methylalaninamide (racemate)




Analogously to Example 1, 25 mg (69 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 156A) and 26 mg (76 μmol) of the compound of Example 64A were employed. Purification by HPLC [Method 7] gave 35 mg (83% of theory) of the title compound.
LC-MS [Method 5]: Rt=0.97 min; MS [ESIpos]: m/z=613 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 3H), 1.38 (s, 3H), 4.53-4.66 (m [AB], 2H), 5.03 (s, 2H), 5.70 (d, 1H), 6.97 (br. s., 1H), 7.01 (br. s., 1H), 7.02-7.18 (m, 3H), 7.26-7.39 (m, 3H), 7.44-7.51 (m, 2H), 7.53 (s, 4H), 8.12 (s, 1H), 9.01 (d, 1H).
Example 34
N2-{(2-Chlorophenyl) [({3-(4-chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]acetyl}-2-methylalaninamide (racemate)




Analogously to Example 1, 25 mg (72 μmol) of the compound of Example 11A and 27 mg (79 μmol) of the compound of Example 64A were employed. Purification by HPLC [Method 7] gave 34 mg (79% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.01 min; MS [ESIpos]: m/z=599 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 3H), 1.39 (s, 3H), 4.54-4.66 (m [AB], 2H), 5.69 (d, 1H), 6.85 (dq, 1H), 6.96 (br. s., 1H), 7.02 (br. s., 1H), 7.17 (dq, 1H), 7.32-7.39 (m, 2H), 7.44-7.51 (m, 2H), 7.61-7.70 (m, 4H), 8.12 (s, 1H), 9.02 (d, 1H).
Example 35
N2-[(2-Chlorophenyl)({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)acetyl]-2-methylalaninamide (racemate)




Analogously to Example 32, 20 mg (33 μmol) of the compound of Example 34 were hydrogenated and purified. This gave 11 mg (54% of theory) of the title compound.
LC-MS [Method 5]: Rt=0.98 min; MS [ESIpos]: m/z=601 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 3H), 1.38 (s, 3H), 2.59-2.66 (m, 2H), 3.98 (t, 2H), 4.48-4.62 (m [AB], 2H), 5.68 (d, 1H), 6.96 (br. s, 1H), 7.01 (br. s, 1H), 7.31-7.40 (m, 2H), 7.42-7.52 (m, 2H), 7.65 (q, 4H), 8.10 (s, 1H), 8.97 (d, 1H).
Example 36
N2-[({[3-(4-Chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino)(2,3-dichlorophenyl)acetyl]-2-methylalaninamide (racemate)




Analogously to Example 1, 25 mg (69 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 156A) and 28 mg (76 μmol) of the compound of Example 65A were reacted. Purification by HPLC [Method 7] gave 35 mg (78% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.03 min; MS [ESIpos]: m/z=647 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.36 (s, 3H), 1.37 (s, 3H), 4.54-4.68 (m [AB], 2H), 5.02 (s, 2H), 5.75 (d, 1H), 6.97 (br. s., 1H), 6.99 (br. s., 1H), 7.01-7.07 (m, 1H), 7.07-7.19 (m, 2H), 7.26-7.34 (m, 1H), 7.39 (t, 1H), 7.46 (dd, 1H), 7.53 (s, 4H), 7.62 (dd, 1H), 8.21 (s, 1H), 9.08 (d, 1H).
Example 37
N2-{[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop-1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino](2,3-dichlorophenyl)acetyl}-2-methylalaninamide (racemate)




Analogously to Example 1, 25 mg (72 μmol) of the compound of Example 11A and 29 mg (79 μmol) of the compound of Example 65A were reacted. Purification by HPLC [Method 7] gave 35 mg (77% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.06 min; MS [ESIpos]: m/z=633 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (s, 3H), 1.38 (s, 3H), 4.55-4.66 (m [AB], 2H), 5.74 (d, 1H), 6.85 (dq, 1H), 6.96 (br. s., 1H), 7.00 (br. s., 1H), 7.14-7.21 (m, 1H), 7.39 (t, 1H), 7.45 (dd, 1H), 7.60-7.70 (m, 5H), 8.22 (s, 1H), 9.09 (d, 1H).
Example 38
Methyl N-{(3S)-3-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninate




Analogously to Example 1, 93 mg (0.26 mmol) of the compound of Example 8A and 108 mg (0.29 mmol) of the compound of Example 67A gave the title compound. Yield: 134 mg (77% of theory).
LC-MS [Method 3]: Rt=1.32 min; MS [ESIpos]: m/z=680 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.18 (s, 3H), 1.23 (s, 3H), 2.56-2.67 (m, 2H), 3.44 (s, 3H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.21-4.34 (m, 1H), 4.48 (s, 2H), 5.26 (q, 1H), 6.89 (d, 1H), 7.53-7.66 (m, 6H), 7.75 (d, 2H), 8.29 (s, 1H), 8.81 (d, 1H).
Example 39
N-{(3S)-3-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalanine




478 μl (478 μmol) of a 1N aqueous solution of lithium hydroxide were added to a solution of 130 mg (0.19 mmol) of the compound of Example 38 in 5 ml of acetonitrile, and the mixture was stirred at RT overnight. After addition of 1 ml of 1N hydrochloric acid, the entire mixture was separated by preparative HPLC [Method 6]. This gave 103 mg (81% of theory) of the title compound.
LC-MS [Method 1]: Rt=1.97 min; MS [ESIpos]: m/z=666 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.18 (s, 3H), 1.22 (s, 3H), 2.53-2.66 (m, 2H), 3.82 (dd, 1H), 3.92-4.01 (m, 1H), 4.20-4.33 (m, 1H), 4.48 (s, 2H), 5.27 (q, 1H), 6.90 (d, 1H), 7.50-7.57 (m, 1H), 7.57-7.65 (m, 5H), 7.75 (d, 2H), 8.10 (s, 1H), 8.81 (d, 1H), 12.15 (s, 1H).
Example 40
N2-{(3S)-3-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-3-[3-(trifluoromethyl)phenyl]propanoyl}-2-methylalaninamide




A mixture of 50 mg (75 μmol) of the compound of Example 39, 29 mg (0.15 mmol) of EDC and 20 mg (0.15 mmol) of HOBt in 2 ml of DMF was stirred at RT for 20 min and then poured into 5 ml of ammonia (35% strength solution in water). The reaction mixture was stirred at RT for 30 min and then concentrated on a rotary evaporator, acidified with 2.5 N hydrochloric acid and separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 42 mg (84% of theory) of the title compound.
LC-MS [Method 1]: Rt=1.85 min; MS [ESIpos]: m/z=665 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.21 (s, 3H), 1.22 (s, 3H), 2.56-2.68 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.19-4.33 (m, 1H), 4.42-4.54 (m [AB], 2H), 5.23-5.32 (m, 1H), 6.79 (br. s., 1H), 6.86-6.96 (m, 1H), 7.52-7.58 (m, 1H), 7.58-7.66 (m, 6H), 7.75 (d, 2H), 7.90 (s, 1H), 8.82 (d, 1H).
Example 41
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(1-hydroxy-2-methylpropan-2-yl)-2-[3-(trifluoromethyl)phenyl]-acetamide (diastereomer 1)




A mixture of 50 mg (0.14 mmol) of the compound of Example 8A, 67 mg (0.21 mmol) of the compound of Example 50A, 39 mg (0.21 mmol) of EDC, 28 mg (0.21 mmol) of HOBt and 48 μl (0.27 mmol) of N,N′-diisopropylethylamine in 1.3 ml of DMF was stirred at RT overnight, 1 ml of 1N hydrochloric acid was then added and the mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 61 mg (70% of theory) of the title compound.
LC-MS [Method 4]: Rt=2.38 min; MS [ESIpos]: m/z=638 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.14 (s, 3H), 1.15 (s, 3H), 3.28-3-34 (m, 1H), 3.39-3.46 (m, 1H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.19-4.33 (m, 1H), 4.54-4.66 (m [AB], 2H), 4.78 (t, 1H), 5.63 (d, 1H), 6.89 (d, 1H), 7.56-7.68 (m, 4H), 7.69-7.76 (m, 3H), 7.79 (s, 1H), 7.99 (s, 1H), 8.93 (d, 1H).
Example 42
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(1-hydroxy-2-methylpropan-2-yl)-2-[3-(trifluoromethyl)phenyl]-acetamide (diastereomer 2)




Analogously to Example 41, 50 mg (0.14 mmol) of the compound of Example 8A and 67 mg (0.21 mmol) of the compound of Example 51A were used to prepare the title compound. This gave 65 mg (75% of theory).
LC-MS [Method 3]: Rt=1.27 min; MS [ESIpos]: m/z=638 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.14 (s, 3H), 1.15 (s, 3H), 3.29-3.34 (m, 1H), 3.40-3.46 (m, 1H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.19-4.33 (m, 1H), 4.60 (s, 2H), 4.78 (t, 1H), 5.64 (d, 1H), 6.90 (d, 1H), 7.55-7.67 (m, 4H), 7.69-7.77 (m, 3H), 7.78 (br. s, 1H), 7.98 (s, 1H), 8.93 (d, 1H).
Example 43
2-({[3-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-N-(1-hydroxy-2-methylpropan-2-yl)-2-[3-(trifluoromethyl)phenyl]acetamide (enantiomer 1)




Analogously to Example 1, 25 mg (79 μmol) of the compound of Example 15A and 28 mg (87 μmol) of the compound of Example 50A were employed. Purification by HPLC [Method 7] gave 30 mg (65% of theory) of the title compound.
LC-MS [Method 5]: Rt=0.99 min; MS [ESIpos]: m/z=590 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.14 (s, 3H), 1.15 (s, 3H), 3.19 (s, 3H), 3.28-about 3.33 (m, 1H), 3.39-3.47 (m, 1H), 3.54 (t, 2H), 3.97 (t, 2H), 4.56 (s, 2H), 4.78 (t, 1H), 5.63 (d, 1H), 7.26 (d, 1H), 7.56 (d, 1H), 7.57-7.62 (m, 1H), 7.63-7.68 (m, 1H), 7.71 (d, 1H), 7.78 (s, 1H), 7.99 (s, 1H), 8.93 (d, 1H).
Example 44
2-({[3-(5-Chloro-2-thienyl)-4-(2-methoxyethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino)-N-(1-hydroxy-2-methylpropan-2-yl)-2-[3-(trifluoromethyl)phenyl]acetamide (enantiomer 2)




Analogously to Example 1, 25 mg (79 μmol) of the compound of Example 15A and 28 mg (87 μmol) of the compound of Example 51A were employed. Purification by HPLC [Method 7] gave 33 mg (71% of theory) of the title compound.
LC-MS [Method 5]: Rt=0.99 min; MS [ESIpos]: m/z=590 (M+H)+
Example 45
2-(2-Chlorophenyl)-2-({[3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-N-(2-methoxyethyl)acetamide (racemate)




Analogously to Example 1, 25 mg (69 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 156A) and 21 mg (76 μmol) of the compound of Example 66A were employed. Purification by HPLC [Method 7] gave 35 mg (86% of theory) of the title compound.
LC-MS [Method 5]: Rt=1.03 min; MS [ESIpos]: m/z=586 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.22 (s, 3H), 3.22-3.28 (m, 2H), 3.34-3.38 (m, 2H), 4.51-4.67 (m [AB], 2H), 5.03 (s, 2H), 5.72 (d, 1H), 7.04 (dt, 1H), 7.08-7.19 (m, 2H), 7.26-7.39 (m, 3H), 7.41-7.49 (m, 2H), 7.53 (s, 4H), 8.34 (t, 1H), 8.93 (d, 1H).
Example 46
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[2-(trifluoromethyl)phenyl]acetamide (diastereomer mixture)




47 mg (0.25 mmol) of EDC were added to a mixture of 50 mg (0.14 mmol) of the compound of Example 8A and 33 mg (0.25 mmol) of HOBt in 2.9 ml of DMF, and the mixture was stirred at RT for 20 min 49 mg (0.16 mmol) of the compound of Example 52A and 57 μl (0.33 mmol) of N,N′-diisopropylethylamine were added, and the mixture was stirred overnight. After addition of 1 ml of 1N hydrochloric acid, the reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 24 mg (28% of theory) of the title compound as a diastereomer mixture.
LC-MS [Method 3]: Rt=1.11 min; MS [ESIpos]: m/z=610 (M+H)+
By preparative chromatography on a chiral phase (Method 10), the two diastereomers were separated: see Example 47 and Example 48.
Example 47
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[2-(trifluoromethyl)phenyl]acetamide (diastereomer 1)




First-eluting diastereomer (11 mg) from the chromatographic diastereomer separation according to Method 10 of 24 mg of the compound of Example 46.
Chiral analytical HPLC [Method 11]: Rt=1.87 min
LC-MS [Method 1]: Rt=1.78 min; MS [ESIpos]: m/z=610 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.08-3.24 (m, 2H), 3.36-3.45 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.19-4.35 (m, 1H), 4.48 (d, 1H), 4.62 (d, 1H), 4.67 (t, 1H), 5.69 (d, 1H), 6.92 (d, 1H), 7.50-7.58 (m, 1H), 7.60-7.66 (m, 3H), 7.67-7.78 (m, 4H), 8.17 (t, 1H), 9.03 (d, 1H).
Example 48
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[2-(trifluoromethyl)phenyl]acetamide (diastereomer 2)




Last-eluting diastereomer (10 mg) from the chromatographic diastereomer separation according to Method 10 of 24 mg of the compound of Example 46.
Chiral analytical HPLC [Method 11]: Rt=4.12 min
LC-MS [Method 1]: Rt=1.76 min; MS [ESIpos]: m/z=610 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.07-3.24 (m, 2H), 3.36-3.46 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.34 (m, 1H), 4.47 (d, 1H), 4.59-4.69 (m, 2H), 5.69 (d, 1H), 6.90 (d, 1H), 7.54 (t, 1H), 7.60-7.66 (m, 3H), 7.67-7.77 (m, 4H), 8.17 (t, 1H), 9.04 (d, 1H).
Example 49
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer mixture)




Analogously to Example 46, 30 mg (82 μmol) of the compound of Example 8A and 29 mg (98 μmol) of the compound of Example 54A were used to prepare the title compound. This gave 37 mg (74% of theory) as diastereomer mixture.
LC-MS [Method 3]: Rt=1.17 min; MS [ESIpos]: m/z=610 (M+H)+
By preparative chromatography on a chiral phase (Method 10), the two diastereomers were separated: see Examples 50 and 51.
Example 50
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer 1)




First-eluting diastereomer (11 mg) from the chromatographic diastereomer separation according to Method 10 of 37 mg of the compound of Example 49.
Chiral analytical HPLC [Method 11]: Rt=2.32 min
LC-MS [Method 4]: Rt=2.29 min; MS [ESIpos]: m/z=610 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.01-3.12 (m, 1H), 3.14-3.25 (m, 1H), 3.36-3.43 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.32 (m, 1H), 4.53-4.66 (m [AB], 2H), 4.72 (t, 1H), 5.61 (d, 1H), 6.90 (s, 1H), 7.56-7.69 (m, 4H), 7.70-7.77 (m, 3H), 7.80 (s, 1H), 8.54 (t, 1H), 9.04 (d, 1H).
Example 51
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer 2)




Last-eluting diastereomer (13 mg) from the chromatographic diastereomer separation according to Method 10 of 37 mg of the compound of Example 49.
Chiral analytical HPLC [Method 11]: Rt=4.01 min
LC-MS [Method 3]: Rt=1.16 min; MS [ESIpos]: m/z=610 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.01-3.11 (m, 1H), 3.15-3.25 (m, 1H), 3.35-3.44 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.33 (m, 1H), 4.52-4.66 (m [AB], 2H), 4.71 (t, 1H), 5.61 (d, 1H), 6.88 (d, 1H), 7.55-7.69 (m, 4H), 7.70-7.77 (m, 3H), 7.80 (s, 1H), 8.54 (t, 1H), 9.04 (d, 1H).
Example 52
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-2-[3-(trifluoromethoxy)phenyl]acetamide (diastereomer mixture)




Analogously to Example 1 (reaction time: overnight), 40 mg (0.11 mmol) of the compound of Example 8A and 38 mg (0.12 mmol) of the compound of Example 55A were used to prepare the title compound. This gave 64 mg (93% of theory) as a diastereomer mixture.
LC-MS [Method 3]: Rt=1.20 min; MS [ESIpos]: m/z=626 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.02-3.12 (m, 1H), 3.14-3.24 (m, 1H), 3.34-3.43 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.33 (m, 1H), 4.53-4.65 (m [AB], 2H), 4.72 (t, 1H), 5.57 (d, 1H), 6.90 (dd, 1H, interpreted as 1 d each (6.889 and 6.904) per diastereomer), 7.29 (d, 1H), 7.42 (s, 1H), 7.44-7.52 (m, 2H), 7.62 (d, 2H), 7.71-7.78 (m, 2H), 8.54 (t, 1H), 9.00 (d, 1H).
Example 53
(3S)-3-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[2-(trifluoromethyl)phenyl]propanamide




Analogously to Example 46, 35 mg (96 μmol) of the compound of Example 8A and 36 mg (115 μmol) of the compound of Example 56A were used to prepare the title compound. This gave 25 mg (42% of theory).
LC-MS [Method 4]: Rt=2.18 min; MS [ESIpos]: m/z=624 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.45 (dd, 1H), 2.58 (dd, 1H), 3.09 (q, 2H), 3.31-3.38 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.19-4.33 (m, 1H), 4.39-4.51 (m, 2H), 4.64 (t, 1H), 5.46-5.54 (m, 1H), 6.89 (d, 1H), 7.42-7.51 (m, 1H), 7.59-7.70 (m, 5H), 7.74 (d, 2H), 7.82 (t, 1H), 8.76 (d, 1H).
Example 54
(3S)-3-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-hydroxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide




Analogously to Example 1, 74 mg (0.20 mmol) of the compound of Example 8A and 70 mg (0.22 mmol) of the compound of Example 57A were used to prepare the title compound. This gave 103 mg (81% of theory).
LC-MS [Method 3]: Rt=1.16 min; MS [ESIpos]: m/z=624 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.57-2.64 (m, 2H), 3.03 (q, 2H), 3.23-3.29 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.35 (m, 1H), 4.48 (s, 2H), 4.57-4.63 (m, 1H), 5.27 (q, 1H), 6.89 (br. s., 1H), 7.51-7.66 (m, 6H), 7.70-7.78 (m, 2H), 7.93 (t, 1H), 8.81 (d, 1H).
Example 55
(3S)-3-({[3-(4-Chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}-amino)-N-(2-hydroxyethyl)-3-[2-(trifluoromethyl)phenyl]propanamide




Analogously to Example 46, 50 mg (0.17 mmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 88A) and 64 mg (0.20 mmol) of the compound of Example 56A were used to prepare the title compound. This gave 43 mg (46% of theory).
LC-MS [Method 4: Rt=1.99; MS [ESIpos]: m/z=552 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.50-0.66 (m, 2H), 0.81-0.95 (m, 2H), 2.43 (dd, 1H), 2.54-2.60 (m, 1H), 3.07 (q, 2H), 3.16 (tt, 1H), 3.28-3.38 (m, 2H), 4.32-4.43 (m [AB], 2H), 4.63 (t, 1H), 5.41-5.52 (m, 1H), 7.41-7.50 (m, 1H), 7.55-7.70 (m, 5H), 7.76-7.86 (m, 3H), 8.76 (d, 1H).
Example 56
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-methoxyethyl)-2-[2-(trifluoromethyl)phenyl]acetamide (diastereomer mixture)




Analogously to Example 46, 30 mg (82 μmol) of the compound of Example 8A and 31 mg (98 μmol) of the compound of Example 53A were used to prepare the title compound. This gave 42 mg (82% of theory).
LC-MS [Method 1]: Rt=1.93 min; MS [ESIpos]: m/z=624 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.23 (d, 3H, interpreted as 1 s each per diastereomer), 3.20-3.29 (m, 2H), 3.29-3.40 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.34 (m, 1H), 4.47 (dd, 1H), 4.62 (dd, 1H), 5.69 (dd, 1H, interpreted as 1 d each per diastereomer), 6.91 (dd, 1H, interpreted as 1 d each per diastereomer), 7.55 (t, 1H), 7.59-7.66 (m, 3H), 7.67-7.79 (m, 4H), 8.27 (t, 1H), 9.04 (dd, 1H, interpreted as 1 d each per diastereomer).
Example 57
(3S)-3-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-methoxyethyl)-3-[3-(trifluoromethyl)phenyl]propanamide




Analogously to Example 46, 50 mg (0.14 mmol) of the compound of Example 8A and 54 mg (0.16 mmol) of the compound of Example 59A were used to prepare the title compound. This gave 77 mg (88% of theory).
LC-MS [Method 3]: Rt=1.25 min; MS [ESIpos]: m/z=638 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.57-2.65 (m, 2H), 3.04-3.24 (m, 4H), 3.15 (s, 3H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.21-4.34 (m, 1H), 4.48 (s, 2H), 5.23-5.32 (m, 1H), 6.89 (d, 1H), 7.51-7.65 (m, 6H), 7.71-7.79 (m, 2H), 8.01 (t, 1H), 8.82 (d, 1H).
Example 58
(3S)-3-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-(2-methoxyethyl)-3-[2-(trifluoromethyl)phenyl]propanamide




Analogously to Example 46, 35 mg (96 μmol) of the compound of Example 8A and 38 mg (115 μmol) of the compound of Example 58A were used to prepare the title compound. This gave 53 mg (87% of theory).
LC-MS [Method 4]: Rt=2.37 min; MS [ESIpos]: m/z=638 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.45 (dd, 1H), 2.58 (dd, 1H), 3.14-3.20 (m, 2H), 3.21 (s, 3H), 3.25-3.29 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.21-4.32 (m, 1H), 4.44 (s, 2H), 5.45-5.55 (m, 1H), 6.89 (d, 1H), 7.44-7.50 (m, 1H), 7.59-7.70 (m, 5H), 7.72-7.77 (m, 2H), 7.90 (t, 1H), 8.77 (d, 1H).
Example 59
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-[2-(trifluoromethoxy)ethyl]-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer 1)




Analogously to Example 1, 37 mg (0.10 mmol) of the compound of Example 8A and 45 mg (0.12 mmol) of the compound of Example 60A were used to prepare the title compound. This gave 61 mg (88% of theory).
LC-MS [Method 1]: Rt=2.26 min; MS [ESIpos]: m/z=678 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.30-3.40 (m, 1H), 3.40-3.51 (m, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 3.98-4.07 (m, 2H), 4.20-4.32 (m, 1H), 4.54-4.65 (m [AB], 2H), 5.60 (d, 1H), 6.90 (d, 1H), 7.56-7.64 (m, 3H), 7.65-7.69 (m, 1H), 7.70-7.77 (m, 3H), 7.78 (br. s, 1H), 8.76 (t, 1H), 9.08 (d, 1H).
Example 60
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-N-[2-(trifluoromethoxy)ethyl]-2-[3-(trifluoromethyl)phenyl]acetamide (diastereomer 2)




Analogously to Example 1, 50 mg (0.14 mmol) of the compound of Example 8A and 60 mg (0.16 mmol) of the compound of Example 61A were used to prepare the title compound. This gave 73 mg (79% of theory)
LC-MS [Method 1]: Rt=2.26 min; MS [ESIpos]: m/z=678 (M+H)+
1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.31-3.40 (m, 1H), 3.40-3.50 (m, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 3.97-4.07 (m, 2H), 4.19-4.35 (m, 1H), 4.52-4.68 (m [AB], 2H), 5.60 (d, 1H), 6.88 (d, 1H), 7.56-7.65 (m, 3H), 7.65-7.69 (m, 1H), 7.70-7.76 (m, 3H), 7.79 (s, 1H), 8.76 (t, 1H), 9.08 (d, 1H).
B. EVALUATION OF THE PHARMACOLOGICAL ACTIVITY
Abbreviations


    EDTA ethylenediaminetetraacetic acid
    DMEM Dulbecco's Modified Eagle Medium
    FCS foetal calf serum
    HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid
    SmGM Smooth Muscle Cell Growth Media
    Tris-HCl 2-amino-2-(hydroxymethyl)-1,3-propanediol hydrochloride
    UtSMC Uterine Smooth Muscle Cells


The pharmacological action of the compounds according to the invention can be shown in the following assays:
B-1. Cellular In Vitro Assay for Determining the Vasopressin Receptor Activity
The identification of agonists and antagonists of the V1a and V2 vasopressin receptors from humans and rats and also the quantification of the activity of the substances described here takes place using recombinant cell lines. These cells derive originally from a hamster's ovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC: American Type Culture Collection, Manassas, Va. 20108, USA). The test cell lines constitutively express a modified form of the calcium-sensitive photoprotein aequorin, which, after reconstitution with the cofactor coelenterazine, emits light when there are increases in the free calcium concentration (Rizzuto R., Simpson A. W., Brini M., Pozzan T.; Nature 358 (1992) 325-327). In addition, the cells are stably transfected with the human or rat V1a or V2 receptors. In the case of the Gs-coupling V2 receptors, the cells are stably transfected with a further gene, which codes for the promiscuous Gα16 protein (Amatruda T. T., Steele D. A., Slepak V. Z., Simon M A., Proc. Na. Acad. Sci. USA 88 (1991), 5587-5591), either independently or as a fusion gene. The resulting vasopressin receptor test cells react to stimulation of the recombinantly expressed vasopressin receptors by intracellular release of calcium ions, which can be quantified by the resulting aequorin luminescence using a suitable luminometer (Milligan G., Marshall F., Rees S., Trends in Pharmaco. Sci. 17 (1996) 235-237).
Test Procedure:
On the day before the assay, the cells are plated out in culture medium (DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES) in 384-well microtiter plates and kept in a cell incubator (96% atmospheric humidity, 5% v/v carbon dioxide, 37° C.). On the day of the assay, the culture medium is replaced by a Tyrode solution (140 mM sodium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 2 mM calcium chloride, 20 mM glucose, 20 mM HEPES), which additionally contains the cofactor coelenterazine (50 μM), and the microtiter plate is then incubated for a further 3-4 hours. The test substances in various concentrations are placed for 10 to 20 minutes in the wells of the microtiter plate before the agonist [Arg8]-vasopressin is added, and the resulting light signal is measured immediately in the luminometer. The IC50 values are calculated using the GraphPad PRISM computer program (Version 3.02).
Table A below lists representative IC50 values for the compounds according to the invention transfected with the human V1a or V2 receptor:









TABLE A





Example No.
IC50 hV1a [μM]
IC50 hV2 [μM]

















1
0.0092
0.058


3
0.554
0.467


4
0.0019
0.0041


5
0.042
1.17


6
0.047
0.324


10
0.15
0.96


11
0.028
0.497


12
0.024
0.182


14
0.053
0.009


15
0.012
0.31


16
0.524
0.262


17
1.42
0.022


18
0.0012
0.0019


19
0.0006
0.0011


20
0.0024
0.0045


21
0.0010
0.0008


22
0.0012
0.0027


25
0.502
0.282


26
0.0017
0.0023


28
1.38
0.346


29
0.0010
0.0033


31
0.0078
1.18


32
0.0071
1.27


33
0.017
1.05


35
0.0089
0.655


36
0.0882
0.78


38
0.0328
0.0386


39
0.0049
0.0008


40
0.0111
0.0081


41
0.0015
0.0036


42
0.038
0.158


43
0.060
1.60


49
0.0022
0.0076


52
0.0097
0.042


53
0.0009
0.0026


54
0.0038
0.0026


55
0.0060
0.569


56
0.0030
0.144


57
0.0145
0.0074


58
0.0035
0.136


59
0.136
0.061


60
0.0030
0.0197









B-2. Cellular In Vitro Assay for Detecting the Action of Vasopressin V1a Receptor Antagonists on the Regulation of Pro-Fibrotic Genes
The cell line H9C2 described as a cardiomyocyte type (American Type Culture Collection ATCC No. CRL-1446), isolated from rat cardiac tissue, endogenously expresses the vasopressin VIA receptor AVPR1A in high copy number, whereas the AVPR2 expression cannot be detected. For cell assays for the inhibition of the AVPR1A receptor-dependent regulation of gene expression by receptor antagonists, the procedure is as follows:
H9C2 cells are seeded in 12-well microtiter plates for cell culture, at a cell density of 100 000 cells/well, in 1.0 ml of Opti-MEM medium (Invitrogen Corp., Carlsbad Calif., USA, Cat. No. 11058-021) with 2% FCS and 1% penicillin/streptomycin solution (Invitrogen, Cat. No. 10378-016), and held in a cell incubator (96% atmospheric humidity, 5% v/v carbon dioxide, 37° C.). After 24 hours, sets of three wells (triplicate) are charged with vehicle solution (negative control), vasopressin solution ([Arg8]-vasopressin acetate, Sigma, Cat. No. V9879) or test substances (dissolved in vehicle: water with 20% by volume ethanol) and vasopressin solution. In the cell culture, the final vasopressin concentration is 0.05 μM. The test substance solution is added to the cell culture in small volumes, and so a final concentration of 0.1% of ethanol in the cell assay is not exceeded. After an incubation time of 6 hours, the culture supernatant is drawn off under suction, the adherent cells are lysed in 250 μl of RLT buffer (Qiagen, Ratingen, Cat. No. 79216), and the RNA is isolated from this lysate using the RNeasy kit (Qiagen, Cat. No. 74104). This is followed by DNAse digestion (Invitrogen, Cat. No. 18068-015), cDNA synthesis (Promaga, ImProm-II Reverse Transcription System, Cat. No. A3800) and RTPCR (pPCR MasterMix RT-QP2X-03-075 from Eurogentec, Seraing, Belgium). All procedures take place in accordance with the working protocols of the test reagents' manufacturers. The primer sets for the RTPCR are selected on the basis of the mRNA gene sequences (NCBI Genbank Entrez Nucleotide Data Base) using the Primer3Plus program with 6-FAM TAMRA-labelled probes. The RTPCR for determining the relative mRNA expression in the cells of the various assay batches is carried out using the Applied Biosystems ABI Prism 7700 Sequence Detector in 96-well or 384-well microtiter plate format in accordance with the instrument operating instructions. The relative gene expression is represented by the delta-delta Ct value [Applied Biosystems, User Bulletin No. 2 ABI Prism 7700 SDS Dec. 11, 1997 (updated 10/2001)] with reference to the level of expression of the ribosomal protein L-32 gene (Genbank Acc. No. NM—013226) and the threshold Ct value of Ct=35.
B-3. In Vivo Assay for Detecting the Cardiovascular Effect: Blood Pressure Measurement on Anaesthetized Rats (Vasopressin ‘Challenge’ Model)
In male Sprague-Dawley rats (250-350 g body weight) under ketamine/xylazine/pentobarbital injection anaesthesia, polyethylene tubes (PE-50; Intramedic®), which are prefilled with heparin-containing (500 IU/ml) isotonic sodium chloride solution, are introduced into the jugular vein and the femoral vein and then tied in. Via one venous access, with the aid of a syringe, argininevasopressin is injected; the test substances are administered via the second venous access. For determination of the systolic blood pressure, a pressure catheter (Millar SPR-320 2F) is tied into the carotid artery. The arterial catheter is connected to a pressure transducer which feeds its signals to a recording computer equipped with suitable recording software. In a typical experiment the experimental animal is administered 3-4 successive bolus injections at intervals of 10-15 min with a defined amount of argininevasopressin (30 ng/kg) in isotonic sodium chloride solution and, when the blood pressure has reached initial levels again, the substance under test is administered as a bolus, with subsequent ongoing infusion, in a suitable solvent. After this, at defined intervals (10-15 min), the same amount of vasopressin as at the start is administered again. On the basis of the blood pressure values, a determination is made of the extent to which the test substance counteracts the hypertensive effect of the vasopressin. Control animals receive only solvent instead of the test substance.
Following intravenous administration, the compounds of the invention, in comparison to the solvent controls, bring about an inhibition in the blood pressure increase caused by arginine-vasopressin.
B-4. In Vivo Assay for Detecting the Cardiovascular Effect: Diuresis Investigations on Conscious Rats in Metabolism Cages
Wistar rats (220-400 g body weight) are kept with free access to feed (Altromin) and drinking water. During the experiment, the animals are kept with free access to drinking water for 4 to 8 hours individually in metabolism cages suitable for rats of this weight class (Tecniplast Deutschland GmbH, D-82383 Hohenpeiβenberg). At the beginning of the experiment, the animals are administered the substance under test in a volume of 1 to 3 ml/kg body weight of a suitable solvent by means of gavage into the stomach. Control animals receive only solvent. Controls and substance tests are carried out in parallel on the same day. Control groups and substance-dose groups each consist of 4 to 8 animals. During the experiment, the urine excreted by the animals is collected continuously in a receiver at the base of the cage. The volume of urine per unit time is determined separately for each animal, and the concentration of the sodium and potassium ions excreted in the urine is measured by standard methods of flame photometry. To obtain a sufficient volume of urine, the animals are given a defined amount of water by gavage at the beginning of the experiment (typically 10 ml per kilogram of body weight). Before the beginning of the experiment and after the end of the experiment, the body weight of the individual animals is determined.
Following oral administration, in comparison with control animals, the compounds of the invention bring about an increased excretion of urine, which is based essentially on an increased excretion of water (aquaresis).
B-5. In Vivo Assay for Detecting the Cardiovascular Effect: Haemodynamic Investigations on Anaesthetized Dogs
Male or female mongrel dogs (Mongrels, Marshall BioResources, USA) with a weight of between 20 and 30 kg are anaesthetized with pentobarbital (30 mg/kg iv, Narcoren®, Merial, Germany) for the surgical interventions and the haemodynamic and functional investigation termini. Alcuronium chloride (Alloferin®, ICN Pharmaceuticals, Germany, 3 mg/animal iv) serves additionally as a muscle relaxant. The dogs are intubated and ventilated with an oxygen/ambient air mixture (40/60%), about 5-6 L/min) Ventilation takes place using a ventilator from Draeger (Sulla 808) and is monitored using a carbon dioxide analyser (Engström).
The anaesthesia is maintained by continual infusion of pentobarbital (50 μag/kg/min); fentanyl is used as an analgesic (10 μg/kg/h). One alternative to pentobarbital is to use isoflurane (1-2% by volume).
In preparatory interventions, the dogs are fitted with a cardiac pacemaker.

    
    
        At a time of 21 days before the first drug testing (i.e. start of experiment), a cardiac pacemaker from Biotronik (Logos®) is implanted into a subcutaneous skin pocket and is contacted with the heart via a pacemaker electrode which is advanced through the external jugular vein, with illumination, into the right ventricle.
        At the same time as the implanting of the pacemaker, through retrograde advancing of 7F biopsy forceps (Cordis) via a sheath introducer (Avanti+®; Cordis) in the fermoral artery, and after atraumatic passage through the aortic valve, there is defined lesion of the mitral valve, with monitoring by echocardiography and illumination. Thereafter all of the accesses are removed and the dog wakes spontaneously from the anaesthesia.
        After a further 7 days (i.e. 14 days before the first drug testing), the above-described pacemaker is activated and the heart is stimulated at a frequency of 220 beats per minute.
    
    


The actual drug testing experiments take place 14 and 28 days after the beginning of pacemaker stimulation, using the following instrumentation:

    
    
        Introduction of a bladder catheter for bladder relief and for measuring the flow of urine
        Attachment of ECG leads to the extremities (for ECG measurement)
        Introduction of a Fluidmedic PE-300 tube filled with sodium chloride solution into the femoral artery. This tube is connected to a pressure sensor (Braun Melsungen, Melsungen, Germany) for measuring the systemic blood pressure
        Introduction of a Millar Tip catheter (type 350 PC, Millar Instruments, Houston, USA) through the left atrium or through a port secured in the carotid artery, for measuring cardiac haemodynamics
        Introduction of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards, Irvine, USA) via the jugular vein into the pulmonary artery, for measuring the cardiac output, oxygen saturation, pulmonary arterial pressures and central venous pressure
        Siting of a venous catheter in the cephalic vein, for infusing pentobarbital, for liquid replacement and for blood sampling (determination of the plasma levels of substance or other clinical blood values)
        Siting of a venous catheter in the saphenous vein, for infusing fentanyl and for administration of substance
        Infusion of vasopressin (Sigma) in increasing dosage, up to a dose of 4 mU/kg/min. The pharmacological substances are then tested with this dosage.
    
    


The primary signals are amplified if necessary (Gould amplifier, Gould Instrument Systems, Valley View, USA or Edwards-Vigilance-Monitor, Edwards, Irvine, USA) and subsequently fed into the Ponemah system (DataSciences Inc, Minneapolis, USA) for evaluation. The signals are recorded continuously throughout the experimental period, and are further processed digitally by said software, and averaged over 30 seconds.
B-6. Determination of the Solubility
Reagents Required:

    
    
        PBS buffer pH 6.5: 90.00 g of NaCl p.a. (for example from Merck, Art. No. 1.06404.1000), 13.61 g of KH2PO4 p.a. (for example from Merck, Art. No. 1.04873.1000) and 83.35 g of 1N aqueous sodium hydroxide solution (for example from Bernd Kraft GmbH, Art. No. 01030.4000) are weighed into a 1 liter measuring flask, the flask is filled with distilled water to 1 liter and the mixture is stirred for 1 hour. Using 1N hydrochloric acid (for example from Merck, Art. No. 1.09057.1000) the pH is then adjusted to 6.5.
        PEG/water solution (30:70 v/v): 30 ml of polyethylene glycol 400 (for example from Merck, Art. No. 8.17003.1000) and 70 ml of distilled water are homogenized in a 100 ml measuring flask.
        PEG/PBS buffer pH 6.5 (80:20 v/v): 80 ml of polyethylene glycol 400 (for example from Merck, Art. No. 8.17003.1000) and 20 ml of PBS buffer pH 6.5 are homogenized in a 100 ml measuring flask.
        Dimethyl sulphoxide (for example from Baker, Art. No. 7157.2500)
        Distilled water.
    
    


Preparation of the Starting Solution (Original Solution):
At least 4 mg of the test substance are weighed accurately into a wide-necked 10 mm screw V vial (from Glastechnik Gräfenroda GmbH, Art. No. 8004-WM-H/V150 with fitting screw cap and septum, in a pipetting robot DMSO is added to a concentration of 50 mg/ml and the mixture is shaken for 10 minutes.
Preparation of the Calibration Solutions:
Preparation of the starting solution for calibration solutions (stock solution): With the aid of a pipetting robot, 10 μl of the original solution are transferred into a microtiter plate and made up with DMSO to a concentration of 600 μg/ml. The sample is shaken until everything has gone into solution.
Calibration solution 1 (20 μg/ml): 1000 μl of DMSO are added to 34.4 μl of the stock solution, and the mixture is homogenized.
Calibration solution 2 (2.5 μg/ml): 700 μl of DMSO are added to 100 μl of calibration solution 1, and the mixture is homogenized.
Preparation of the Sample Solutions:
Sample solution for solubilities of up to 5 g/liter in PBS buffer pH 6.5: 10 μl of the original solution are transferred into a microtiter plate, and 1000 μl of PBS buffer pH 6.5 are added.
Sample solution for solubilities of up to 5 g/liter in PEG/water (30:70): 10 μl of the original solution are transferred into a microtiter plate, and 1000 μl of PEG/water (30:70) are added.
Sample solution for solubilities of up to 5 g/liter in PEG/PBS buffer pH 6.5 (80:20): 10 μl of the original solution are transferred into a microtiter plate, and 1000 μl of PEG/PBS buffer pH 6.5 (80:20) are added.
Practice:
The sample solutions prepared in this manner are shaken at 1400 rpm in a temperature-adjustable shaker (for example Eppendorf Thermomixer comfort Art. No. 5355 000.011 with interchangeable block Art. No. 5362.000.019) at 20° C. for 24 hours. In each case 180 μl are taken from these solutions and transferred into Beckman Polyallomer Centrifuge Tubes (Art. No. 343621). These solutions are centrifuged at about 223 000×g for one hour (for example Beckman Optima L-90K Ultracentrifuge with Type 42.2 Ti Rotor at 42 000 rpm). From each of the sample solutions, 100 μl of the supernatant are removed and diluted 1:5 and 1:100 with DMSO. From each dilution, a sample is transferred into a vessel suitable for HPLC analysis.
Analysis:
The samples are analysed by RP-HPLC. Quantification is carried out using a two-point calibration curve of the test compound in DMSO. The solubility is expressed in mg/liter. Analysis sequence: 1) calibration solution 2.5 mg/ml; 2) calibration solution 20 μg/ml; 3) sample solution 1:5; 4) sample solution 1:100.
HPLC Method for Acids:
Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: Phenomenex Gemini C18, 50 mm×2 mm, 5μ; temperature: 40° C.; mobile phase A: water/phosphoric acid pH 2; mobile phase B: acetonitrile; flow rate: 0.7 ml/min; gradient: 0-0.5 min 85% A, 15% B; ramp: 0.5-3 min 10% A, 90% B; 3-3.5 min 10% A, 90% B; ramp: 3.5-4 min 85% A, 15% B; 4-5 min 85% A, 15% B.
HPLC Method for Bases:
Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column: VDSoptilab Kromasil 100 C18, 60 mm×2.1 mm, 3.5μ; temperature: 30° C.; mobile phase A: water+5 ml of perchloric acid/liter; mobile phase B: acetonitrile; flow rate: 0.75 ml/min; gradient: 0-0.5 min 98% A, 2% B; ramp: 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; ramp: 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
Representative solubilities of the compounds of the formula (I) according to the invention are shown in Table B below.










TABLE B








Solubility [mg/l]




PBS buffer



Example
pH 6.5



















6
340



10
360



21
360



31
110



52
100



54
400










C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS
The compounds according to the invention can be converted into pharmaceutical preparations in the following ways:
Tablet:
Composition:
100 mg of the compound according to the invention, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.
Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm
Production:
The mixture of compound according to the invention, lactose and starch is granulated with a 5% strength solution (m/m) of the PVP in water. The granules are dried and then mixed with the magnesium stearate for 5 minutes. This mixture is compressed in a conventional tablet press (see above for format of the tablet). A guideline compressive force for the compression is 15 kN.
Suspension which can be Administered Orally:
Composition:
1000 mg of the compound according to the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.
10 ml of oral suspension correspond to a single dose of 100 mg of the compound according to the invention.
Production:
The Rhodigel is suspended in ethanol, and the compound according to the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.
Solution which can be Administered Orally:
Composition:
500 mg of the compound according to the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400.20 g of oral solution correspond to a single dose of 100 mg of the compound according to the invention.
Production:
The compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention has completely dissolved.
i.v. Solution:
The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution). The solution is sterilized by filtration and used to fill sterile and pyrogen-free injection containers.

## Claims

1. A compound of the formula (I)



in which
A represents a bond or —C(R6AR6B)—,
where
R6A represents hydrogen, (C1-C4)-alkyl or trifluoromethyl,
R6B represents hydrogen or (C1-C4)-alkyl,

R1 represents (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C3-C7)-cycloalkyl,
where (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of deuterium, halogen, cyano, oxo, hydroxy, trifluoromethyl, (C3-C7)-cycloalkyl, (C1-C6)-alkoxy, trifluoromethoxy and phenyl,
in which (C3-C7)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C1-C4)-alkyl, oxo, hydroxy, (C1-C4)-alkoxy and amino,
and
in which (C1-C6)-alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of amino, hydroxy, (C1-C4)-alkoxy, hydroxycarbonyl and (C1-C4)-alkoxycarbonyl
and
in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C1-C4)-alkyl, trifluoromethyl, hydroxy, hydroxymethyl, (C1-C4)-alkoxy, trifluoromethoxy, (C1-C4)-alkoxymethyl, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl and di-(C1-C4)-alkylaminocarbonyl,

and
where (C3-C7)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxy, amino and oxo,

R2 represents benzothienyl, phenyl, thienyl or furyl,
where benzothienyl, phenyl, thienyl and furyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C1-C4)-alkyl, trifluoromethyl, hydroxy, (C1-C4)-alkoxy and trifluoromethoxy,

R3 represents a group of the formula




where
# represents the point of attachment to the nitrogen atom,
L represents (C1-C4)-alkanediyl,
where (C1-C4)-alkanediyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine and (C1-C4)-alkyl,

R7A represents hydrogen or (C1-C4)-alkyl,

R7B represents hydrogen or (C1-C4)-alkyl,
or
R7A and R7B together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle,
R8 represents hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl,
R9 represents hydroxy, trifluoromethoxy, (C1-C4)-alkoxy, hydroxycarbonyl, (C1-C4)-alkoxycarbonyl, aminocarbonyl, mono-(C1-C4)-alkylaminocarbonyl or di-(C1-C4)-alkylaminocarbonyl,

R4 represents phenyl, naphthyl or 5- to 10-membered heteroaryl,
where phenyl, naphthyl and 5- to 10-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C1-C4)-alkyl, difluoromethyl, trifluoromethyl, hydroxy, (C1-C4)-alkoxy, difluoromethoxy and trifluoromethoxy,

R5 represents hydrogen, deuterium, trifluoromethyl or (C1-C4)-alkyl,
and its salts, solvates and solvates of the salts.

2. The compound of claim 1, in which
A represents a bond or —C(R6AR6B)—,
where
R6A represents hydrogen,
R6B represents hydrogen,

R1 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C3-C6)-cycloalkyl,
where (C1-C6)-alkyl and (C2-C6)-alkenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, oxo, hydroxy, trifluoromethyl, (C3-C6)-cycloalkyl, (C1-C4)-alkoxy, trifluoromethoxy and phenyl,
in which (C3-C6)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of methyl, ethyl, oxo, hydroxy, methoxy, ethoxy and amino,
and
in which phenyl may be substituted by a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and aminocarbonyl,

and
where (C3-C6)-cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, methyl, ethyl, methoxy, ethoxy, hydroxy, amino and oxo,

R2 represents phenyl or thienyl,
where phenyl and thienyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy and trifluoromethoxy,

R3 represents a group of the formula




where
# represents the point of attachment to the nitrogen atom,
L represents methylene,
where methylene may be substituted by 1 or 2 methyl substituents,

R7A represents hydrogen or methyl,

R7B represents hydrogen or methyl,
or
R7A and R7B together with the carbon atom to which they are attached form a cyclopropyl ring,
R8 represents hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl,
R9 represents hydroxy, trifluoromethoxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl,

R4 represents phenyl,
where phenyl is substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy,

R5 represents hydrogen or methyl,
and its salts, solvates and solvates of the salts.

3. The compound of claim 1, in which
A represents a bond or —C(R6AR6B)—,
where
R6A represents hydrogen,
R6B represents hydrogen,

R1 represents (C2-C4)-alkyl, (C2-C4)-alkenyl or cyclopropyl, where (C2-C4)-alkyl and (C2-C4)-alkenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, oxo, hydroxy and trifluoromethyl,
R2 represents phenyl,
where phenyl is substituted by a substituent selected from the group consisting of fluorine and chlorine,

R3 represents a group of the formula




where
# represents the point of attachment to the nitrogen atom,
L represents methylene,
R7A represents hydrogen or methyl,

R7B represents hydrogen or methyl,
or
R7A and R7B together with the carbon atom to which they are attached form a cyclopropyl ring,
R8 represents hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl,
R9 represents hydroxy, methoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl,

R4 represents a group of the formula





where
* represents the point of attachment to the group —C(R5)(AC(═O)NHR3)—,
R10 represents hydrogen, chlorine, trifluoromethyl, trifluoromethoxy or methoxy,
R11 represents hydrogen, fluorine, chlorine, trifluoromethyl, trifluoromethoxy or methoxy,
where at least one of the radicals R10 and R11 is different from hydrogen,

R5 represents hydrogen or methyl,
and its salts, solvates and solvates of the salts.

4. A process for preparing compounds of the formula (I) as defined in claim 1, comprising:
[A] coupling a compound of the formula (II)





in which R1 and R2 each have the meanings given in claim 1,
in an inert solvent with activation of the carboxylic acid function with a compound of the formula (III)






in which A, R3, R4 and R5 each have the meanings given in claim 1,

or
[B] reacting a compound of the formula (IV)





in which R1 and R2 each have the meanings given in claim 1,
in an inert solvent in the presence of a base with a compound of the formula (V)






in which A, R3, R4 and R5 each have the meanings given in claim 1
and
X1 represents a leaving group,

or
[C] coupling a compound of the formula (VI)





in which A, R1, R2, R4 and R5 each have the meanings given in claim 1,
in an inert solvent with activation of the carboxylic acid function with a compound of the formula (VII)


H2N—R3  (VII),


in which R3 has the meaning given in claim 1,

and optionally converting the resulting compounds of formula (I) with the appropriate (i) solvents and/or (ii) acids or bases into their solvates, salts and/or solvates of the salts.

5. A pharmaceutical composition comprising a compound of claim 1 and an inert, non-toxic, pharmaceutically suitable auxiliary.

6. The pharmaceutical composition of claim 5, further comprising one or more active substances selected from the group consisting of diuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors and positive-inotropic active substances.

7. A method for the treatment of acute and chronic heart failure, hypervolaemic and euvolaemic hyponatraemia, cirrhosis of the liver, ascites, oedema and the syndrome of inadequate ADH secretion (SIADH) comprising administering to a human or animal in need thereof an effective amount of at least one compound of claim 1.

8. A method for the treatment of acute and chronic heart failure, hypervolaemic and euvolaemic hyponatraemia, cirrhosis of the liver, ascites, oedema and the syndrome of inadequate ADH secretion (SIADH) comprising administering to a human or animal in need thereof an effective amount of at least one pharmaceutical composition of claim 5.